Potential clinical applications of current and future oral forms of desmopressin (Review)
- Authors:
- Published online on: May 29, 2024 https://doi.org/10.3892/etm.2024.12592
- Article Number: 303
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Copyright: © Everaert et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
1. Introduction
Desmopressin is a vasopressin (AVP) receptor 2 (V2) agonist, first synthesised in Prague in the late 1960s by Zaoral et al (1). At the time, the objective was to develop an analogue of the native vasopressin hormone that could be used in the treatment of central diabetes insipidus, avoiding the, mainly V1-mediated, side effects of vasopressin treatment relating to its pressor effects, while maintaining or improving upon its antidiuretic effects. Among several analogues produced and evaluated, desmopressin (1-deamino-8-D-arginine vasopressin) proved to be a triumph in achieving the required efficacy and tolerability profile: ‘Rarely in pharmacology is an agent produced that so specifically enhances the desired effect and simultaneously decreases the side effect’ (2).
To this day, desmopressin is used widely for central diabetes insipidus and in other conditions requiring antidiuretic treatment, including nocturnal enuresis (bedwetting), idiopathic nocturnal polyuria and nocturia (nocturnal voiding) (3).
In the 1970s, a new indication came to light when intravenous administration of high doses of desmopressin was found to raise levels of the clotting factor Factor VIII in healthy volunteers and in patients with mild-to-moderate haemophilia A and von Willebrand's disease (VWD). These are both inherited bleeding disorders characterised by low levels of Factor VIII or von Willebrand factor (a carrier for Factor VIII), leading to impaired blood clotting (4,5). Desmopressin became, and remains, a valuable addition to the treatment armamentarium for these conditions, helping to prevent bleeding episodes via intravenous or intranasal administration (6).
While these uses of desmopressin are well established, there has also been a significant number of reports of clinical benefit in other diverse clinical areas, including distinct but related areas within urology and haematology, as well as completely different disciplines such as oncology and psychiatry/cognition.
In this review, we explore potential for further clinical applications of current and possible future forms of oral desmopressin. We focus on oral formulations, rather than intravenous, subcutaneous or intranasal, because they have the advantages of being easily administered in the home or outpatient setting, are more child friendly, and data suggest that side effects are reduced with oral formulations compared with intranasal ones (7). Because the available oral formulations [tablet and orally disintegrating tablet (ODT)] are used at bioequivalent doses, we refer to them collectively as oral desmopressin. The ODT dissolves under the tongue in a few seconds, whereas the tablet is swallowed.
Desmopressin dosing, formulations and target tissues
The widespread distribution of V2 receptors in the human body (Fig. 1) is itself suggestive that a V2 agonist is likely to have diverse physiological and clinical effects. However, there are two important questions that need to be considered when determining the potential for oral desmopressin to be beneficial in relevant clinical conditions. First, is desmopressin able to reach and/or affect each of the target organs of interest when administered orally? Second, can desmopressin be administered orally at a dose which is both effective and has an acceptable safety profile. Existing oral formulations of desmopressin have low bioavailability. It is currently available as a tablet and as an orally disintegrating (ODT)-see Table I for an overview of dose comparisons across formulations. The ODT has greater bioavailability than the tablet, enabling lower dosing. The ODT formulation has a maximum daily dose of 240 µg for enuresis, while in adults with idiopathic nocturnal polyuria (nocturia) the maximum daily dose is lower and sex-specific at 25 µg for women and 50 µg for men (3). Doses differ in other indications. All formulations, however, demonstrate increased risk of side effects with increasing dose, particularly in older age, when hyponatraemia becomes more likely (8). For current indications requiring higher doses, administration is limited to single or few dosages that are used for specific one-off events, such as surgery or trauma in patients with mild to moderate haemophilia A and VWD.
Pharmacokinetic data indicate that the desmopressin tablet and ODT tablet formulations have a linear dose relationship as follows: 60, 120, 240 and 360 µg ODT correspond to 0.1, 0.2, 0.4 and 0.6 mg tablet, respectively. Regarding bioequivalence of the two oral formulations, all regulatory approvals were based upon bioequivalence studies which showed that lower dosing of the ODT is required due to its higher bioavailability (0.25 vs. 0.16%, as shown in Table I). In addition, it has been proposed that there are some clinically relevant differences between the two oral formulations in terms of their PK/PD profile, such as more predictable dosing (9) and lower food interaction with the ODT (10,11).
A conversion factor between intravenous and oral desmopressin has not been defined; however, the bioavailability of oral desmopressin is approximately 100 times lower than that of IV desmopressin (12). Thus, the IV equipotent dose to 200 µg oral desmopressin would be around 2 µg (13). Each formulation delivers the adequate dose for the approved indications.
We have selected a subset of target organs/tissues for discussion (Table II) based on V2 agonism effects that are well-recognised and understood (in blood and kidney), or on studies in the literature suggesting that desmopressin may be of interest in these areas (ureter, CNS, oncology).
2. Methods
Systematic literature searches of PubMed-indexed literature were conducted using the Silvi.ai software (https://www.silvi.ai/) in each of the potential new areas of interest identified: bleeding control, renal colic, CNS and oncology. Details of the searches are provided in Table III.
Relevant studies in humans, published in English, were included and a table of publications compiled for each area. A small number of additional relevant studies were found during PubMed searches/citation chasing. Summary tables of relevant studies, their characteristics and findings were developed to summarise the literature in therapeutic areas where oral desmopressin use may be feasible, and studies were categorised according to whether findings were supportive of the use of desmopressin or not. Although the literature searches were systematic, the literature cited in this report is not exhaustive due to the wide remit of interest and the fact that some publications could not be accessed without payment-articles were paid for only in the renal colic and CNS searches as these retrieved fewer results. This review therefore provides a broad overview of the evidence across multiple clinical areas. For bleeding disorders, publications specifically of relevance to low-dose desmopressin were sought, since there is a huge body of literature on the approved use of high dose (intravenous/subcutaneous) desmopressin in bleeding disorders and summarising this literature was deemed out of scope because our interest is specifically in oral desmopressin and possible new uses of these formulations. Similarly, for oncology, the doses used in human studies have been above those achievable with oral formulations and only a brief overview of the literature is given.
3. Results of literature review and discussion of findings
Desmopressin and bleeding disorders
Desmopressin (IV, subcutaneous or intranasal) is indicated for use in bleeding disorders (VWD and mild-to-moderate haemophilia type A), with a long history of clinical usage and many publications confirming its efficacy (6,14). Although IV desmopressin is recommended before surgery or for treating severe haemorrhages because very consistent responses are required in these situations, subcutaneous desmopressin can be self-administered and can therefore be used at home to prevent or treat minor bleeding episodes and in women with VWD who have excessive bleeding at menstruation (15). In bleeding disorders, desmopressin is used at high doses (0.3-0.4 µg/kg body weight IV) to increase Factor VIII:C and Factor VIII:Ag in patients with mild to moderate haemophilia A or VWD who are undergoing surgery or following trauma (16). In order to achieve a bioequivalent dose in an average adult, approximately 5,000-7,000 µg desmopressin ODT would be needed.
Intranasal administration is also indicated for patients with these bleeding disorders (17) when they are undergoing surgery, following trauma or for other bleeding episodes such as menorrhagia and epistaxis (nosebleeds). The intranasal spray may be used (300 µg) half an hour before surgery or at bleeding. Using bioequivalence data (Table I), approximately 7,200 µg oral desmopressin ODT would be required to achieve the same dosing as recommended for adults using the intranasal spray (i.e. 10 µg intranasal=240 µg ODT, so 300 µg intranasal=7,200 µg ODT). Currently, the maximum strength of oral ODT is 240 ug, meaning that the use of oral desmopressin in these indications may not be practical. However, there is currently a recall and temporary halt in production of the nasal spray, so there is perhaps a place for oral administration to substitute for nasal administration, as an alternative user-friendly formulation. Some studies suggest that lower absolute doses of desmopressin in children could still achieve efficacy. A study by Akin (18) demonstrated that a lower dose of desmopressin (0.15 µg subcutaneous) was effective in increasing Factor VIII, VWF:RCo and VWF:Ag levels in children with type 1 VWD, and wider use of desmopressin, especially in developing countries, was recommended. In a retrospective study, half dose desmopressin (0.15 µg/kg IV) was also found to be effective in adult bleeding disorder patients undergoing low to moderate risk invasive procedures (19). There are ongoing studies looking at the feasibility of pharmacokinetic-guided dosing of desmopressin since there is considerable pharmacokinetic variability (20,21). There is also variation in clinical response to desmopressin, which was recently demonstrated to be affected by VWF genetic variants (22). These factors suggest that there may be a subset of patients who could benefit from low doses of desmopressin achievable via oral administration, but further studies would be needed in this area.
A systematic review in 2012 noted that desmopressin has been used successfully for prevention of bleeding during pregnancy and postpartum haemorrhage in people with bleeding disorders (23). Most of the studies used 0.3 µg/kg IV infusion (166 cases), while 12 and 20 µg IV desmopressin were used in one case each. Intranasal desmopressin was used in two studies (33 cases) at a dose of 300 µg. Intranasal desmopressin (300 µg for two days) also effectively reduced menstrual blood loss and improved quality of life in patients with abnormal laboratory haemostasis, although the effect of tranexamic acid was greater (24). There may be a role for desmopressin in long-term prophylaxis in patients with vWD, although Factor VIII/von Willebrand factor concentrate is generally the preferred option here (25). It should also be noted that patients with bleeding disorders may develop tolerance to long-term use of desmopressin, and that there are important safety considerations for the long-term use of high-dose desmopressin.
Additional studies-noted during general literature searches-mentioned the use of high dose (0.3-0.4 IV µg/kg in most studies) desmopressin in other bleeding disorders including platelet dysfunction during antiplatelet therapy (26), Hermansky-Pudlak syndrome (27,28), and unclassified bleeding disorders (29,30), but in most cases there was a lack of randomised, controlled trials, and no indication that lower, oral dosing would be effective.
Summary: oral desmopressin in bleeding disorders
An oral formulation of desmopressin would be a more child-friendly formulation for prophylactic use (e.g. before dental surgery) or treatment of bleeding episodes if adequate dosing could be achieved in this patient population. In general, however, bleeding disorders require high doses of desmopressin (0.3 µg/kg IV or 300 µg intranasal) in order for the haematological effects of the drug to be observed. Some studies suggest that half dose (0.15 µg/kg) intravenous desmopressin is still effective, but for oral desmopressin to achieve equivalence, doses would still need to be high.
Desmopressin and bleeding control in patients without a bleeding disorder
In the 1980s, Lawrence Czer's group at the Cedars-Sinai Medical Center in Los Angeles published research indicating that desmopressin reduced bleeding time and improved reoperation rates in patients with mediastinal haemorrhage after cardiopulmonary bypass (31). It was hypothesised that this was due to release of Factor VIII, increase in von Willebrand's factor (an established effect of desmopressin) and improvement in platelet adhesion. Since then, several studies have evaluated desmopressin's potential use in various areas of bleeding control, in patients who do not have a specific bleeding disorder.
A systematic literature review was carried out for studies investigating the use of desmopressin for bleeding control (excluding patients with bleeding disorders-covered in the previous section). Twenty-one studies of interest for which full-text articles were freely available were identified (see supplementary Table SI)-due to an error in the PubMed filtering system, 10 pre-2012 articles were retrieved despite the search string stipulating articles should be from 2012 onwards and these were removed from the final selection. Another five studies were identified through other PubMed searches and citation chasing and were also included in summary Table IV. Studies involved the use of desmopressin for cardiac surgery, endoscopic sinus surgery/rhinoplasty, renal surgery, gastrointestinal surgery and intracerebral haemorrhage.
Cardiac surgery and renal surgery
All except one study of cardiac or renal surgery used the intravenous formulation of desmopressin. Overall, studies in cardiac surgery reported inconsistent findings but generally did not show significant benefit with desmopressin. However, a literature review reported that there are certain subgroups that may benefit from desmopressin use, including patients with demonstrable pre- or perioperative platelet dysfunction as determined by TEG analysis or platelet function assays, those who have received preoperative aspirin within 7 days of surgery, and patients with cardiopulmonary bypass times in excess of 140 min (32). However, further studies are required.
Similar findings were reported in renal surgery (kidney biopsy), with certain subpopulations of patients (serum creatinine ≥1.8 mg/dl and GFR <15 ml/min/1.73 m2) more likely to experience benefit with desmopressin (33,34).
Endoscopic sinus surgery/rhinoplasty. There were five studies of desmopressin in endoscopic sinus surgery or rhinoplasty (35-39)-4 used intranasal desmopressin prior to surgery (20, or 20 and 40 µg), and all found significant benefit with desmopressin, in terms of blood loss and quality of the surgical field. In a randomised trial of low-dose (20 µg) intranasal desmopressin, high-dose (40 µg) intranasal desmopressin and placebo, only the high dose was found to significantly reduce volume of blood loss compared with placebo, as well as doubling the odds of having a good surgical field (35).
Overall, these results suggest that this may be a promising area for future use of the drug at dose levels that could potentially be achieved with oral formulations, although the impact on efficacy of moving from the intranasal formulation to an oral formulation would need to be investigated.
Intracerebral haemorrhage. Neurocritical Care guidelines recommend consideration of desmopressin in antiplatelet-associated intracranial haemorrhage (40). However, the one study in this therapeutic area identified in our search reported no significant benefit with desmopressin (0.4 µg/kg IV) in patients on anti-platelet therapy (41). A recent metanalysis also concluded that the available literature does not support the routine use of desmopressin in the setting of antiplatelet-associated intracerebral haemorrhage (42).
In contrast, a review by Andersen et al (26) found that desmopressin improved bleeding time and increased platelet aggregation in patients with intracerebral or subarachnoid haemorrhage while receiving antiplatelet therapy, as well as in non-cardiac surgery patients and in healthy adults and animals exposed to antiplatelet therapy. There were also some observational data to suggest that desmopressin could reduce haematoma expansion in patients with intracerebral haemorrhage or traumatic brain injury. Nevertheless, the authors considered that randomised controlled trials in these areas are still needed.
In terms of oral desmopressin formulations, as the focus of this review, it is likely that oral administration would not only be unsuited to this kind of acute care setting but also would be unable to achieve equivalent dosing to the intravenous formulation.
Summary: oral desmopressin in bleeding control. Most studies of desmopressin in bleeding control identified in this review used the intravenous formulation at high doses that are unlikely to be achieved with oral formulations. In cardiac and renal surgery, results are inconsistent in any case.
However, the use of oral desmopressin as a preventative measure before endoscopic sinus surgery or rhinoplasty may be feasible given that there have been a number of studies reporting significant benefits for bleeding and for the surgical field with intranasal desmopressin. Results cannot necessarily be extrapolated from localised intranasal delivery to oral administration, however, and studies in this area would be needed.
Desmopressin in renal colic
Renal colic is a common urological condition, with a lifetime risk of around 12% in men and 6% in women (43), although estimates vary across studies and geographic regions. It refers to severe pain resulting from the presence of a stone in the urinary system causing acute obstruction, ureteric dilatation, tensile stretch and spasmodic activity (44-46). The ureter releases prostaglandins in response to the obstruction, rendering nociceptors sensitive to stimuli such as bradykinins that induce pain and other visceral responses such as nausea (47). Prostaglandins also cause increased renal blood flow and down-regulation of the antidiuretic hormone, arginine vasopressin, as well as the contraction of ureteral smooth muscle (47).
In uncomplicated cases of stones up to 10 mm, a conservative approach may be taken, with observation for spontaneous passage for around 4-6 weeks (45). Medical expulsive therapy (MET) is commonly used to increase stone passage rate, decrease time to passage and decrease pain. MET aims to increase ureteral diameter via relaxation of the smooth muscle, and agents including alpha-blockers, calcium channel blockers and prednisolone have been investigated-however, the evidence base for these is limited and some have significant side effects (48-51). MET using alpha-blockers is recommended by the European Association for Urology (EAU) as a potential treatment option for distal ureteral stones >5 mm (51).
Analgesia in renal colic seeks to relax the ureteric smooth muscle and decrease flow within the urinary tract (decreasing the diuretic effect). Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis, are first-line therapy recommended by the EAU and are considered superior to opioids (51). However, they are also associated with unwanted side effects such as gastrointestinal bleeding and renal failure (52).
Since the 1990s, a number of reports have been published documenting an analgesic effect of desmopressin, either used alone or in combination with other therapies, in renal colic patients. A nationwide registry study in Denmark confirmed that desmopressin is prescribed in addition to opioids or NSAIDs, and in some cases as monotherapy, to treat renal colic (47).
The mechanism of pain relief with desmopressin has not been comprehensively investigated but is thought to be a result of one or more of the following possible processes (47): reduction in intra-ureteral mean pressure inside the excretory tract, while kidney blood perfusion is maintained; combating the downregulation of AVP that is brought about by prostaglandin release, encouraging antidiuresis via V2 receptors in the kidney; inhibition of smooth muscle fibre contraction (53); release of ß-endorphin from the hypothalamus in response to desmopressin administration leading to central analgesic effects (54), although this has not been proven, and-as discussed in the section of this review on CNS effects-it is unclear whether desmopressin can cross the blood-brain barrier.
Studies of desmopressin in renal colic
Our systematic literature search for studies investigating the use of desmopressin in renal colic identified 13 relevant studies, including 12 interventional studies. Findings are summarised in Table V, with further study details included in supplementary Table SII.
The majority of studies were conducted in Iran (52,55-62). Two studies used the ODT formulation at 60 µg (59) or 60 and 120 µg (63), while all other interventional studies used the intranasal formulation at doses ranging from 20 µg in one study (56) to 40 µg in all others. Some studies investigated desmopressin monotherapy (60-62,64) but most looked at combination therapy.
Overall, mixed findings are reported regarding the efficacy of desmopressin compared with a range of comparators for pain relief in renal colic, although most studies have reported it to have at least some beneficial effects. Moreover, desmopressin has advantages over many of its comparators in terms of ease of administration and tolerability that mean that it could be useful, especially in combination therapy and for ambulatory pain relief. Some studies have noted a variability in response to intranasal desmopressin across patients (65); oral formulations, which have more reliable dosing, may produce more consistent and/or rapid effects. One study has already demonstrated significantly greater pain relief with 120 µg ODT compared with ketorolac (63), and the number of dropouts due to pain escalation was significantly lower in all groups receiving desmopressin (combination therapy or monotherapy at 60/120 µg). It is also of note that several studies only followed patients for a short period (e.g. 30 min) (64,65), although desmopressin may not reach peak effectiveness until one hour after administration with some formulations (52).
A systematic review and meta-analysis published in 2016 found that most studies were low quality but suggested that desmopressin can be used as an adjuvant therapy in renal colic management in combination with opioids (66). Another recent meta-analysis concluded that desmopressin has lower pain reduction properties than comparators (67). However, it should be noted that some patients do not tolerate first-line therapies well, and as such, effective alternatives are needed. We propose that larger, high-quality studies that follow patient response for a sufficient duration would be beneficial in settling the current confusion and inconsistency surrounding the use of desmopressin in renal colic.
Summary: oral desmopressin in renal colic. Oral desmopressin (60-120 µg ODT) may be useful in renal colic but further, high quality studies are needed to confirm the efficacy of desmopressin in this indication. Oral desmopressin could potentially be used as monotherapy (63) or in combination with NSAIDs-the Pricop study showed mild but statistically significant additive analgesic effects after 30 min of follow-up when ketorolac was used in combination with the lower dose of desmopressin (60 µg ODT) (63), suggesting possible supplementary beneficial effects of this drug combination.
Desmopressin and the central nervous system
Vasopressin, and its sister hormone oxytocin (which differs by only two amino acids), are neuropeptides. Both have been implicated in the modulation of social behaviour and the stress response (68-71).
Since the 1970s, there have been a number of sporadic reports suggesting an effect of desmopressin on different functions of the brain or central nervous system (CNS), including memory, learning and attention. It has also been reported that there may be a central mode of action for desmopressin in its established role as an effective treatment for enuresis: an improvement in short-term memory in children with enuresis treated with desmopressin has been reported (72), and pre-pulse inhibition of startle has been found to be impaired in children with enuresis but restored to normal levels by treatment with desmopressin (73). Similarly, benefits of desmopressin treatment on memory function in patients with diabetes insipidus have been reported (74).
Vasopressin receptors in the CNS
There are three vasopressin receptor subtypes: V1a (primarily responsible for vasoconstriction), V1b (primary involved in activation of the hypothalamic-pituitary-adrenal axis) and V2 (primarily responsible for antidiuresis via action in the kidney).
The action of vasopressin in the brain has predominantly been attributed to V1a receptors which are expressed at higher levels in several areas of the brain (75), and have been associated with pair-bonding, aggression and stress management in animal studies (76). V2 receptors are largely excluded from discussions of CNS effects of vasopressin (68,77) because they are considered not to be expressed at high enough levels in the brain. This may limit the relevance of desmopressin, a V2-selective agonist, for effects on the CNS.
However, V2 receptor expression has been reported in human cerebellum (78) and in rat cerebellum (79), as well as in other areas of the developing rat brain (80). The cerebellum is mainly known for its role in motor control/coordination, but may also be involved in other functions including cognition, emotion (81) and working memory (82).
It is also possible that there is some limited residual effect of desmopressin on V1 receptors in the brain-this would require specific investigation, however. It is thought that desmopressin may be able to activate V1b receptors in certain conditions, such as in people with ACTH-dependent Cushing's disease (83)-this interaction may result from upregulation of V1b receptors (or the aberrant expression of type 2 receptors by neoplastic ACTH-producing cells) (84). Some support for the theory that desmopressin may act centrally also comes from case studies of patients with nephrogenic diabetes insipidus and nocturnal enuresis caused by genetic mutations that prevent the kidney being responsive to AVP (and therefore desmopressin). In a number of reports, these patients have nevertheless experienced improvements in their bedwetting, or transition from bedwetting to nocturia, with desmopressin treatment (85,86). It has therefore been proposed that desmopressin may be able to impact enuresis through effects on arousal or other processes, acting via central rather than renal AVP receptors and possibly via V1 rather than V2 receptors.
Can desmopressin reach the CNS? In general, it is thought that desmopressin is unable to cross the blood-brain (or blood-CSF) barrier when administered intravenously (87-89). However, a mechanism of bidirectional saturable transport across the blood-brain barrier for vasopressin has been demonstrated and, from this, it was concluded that a saturable system exists for brain to blood transport of AVP and some structurally similar peptides (90).
One way to bypass the blood-brain barrier is using intranasal administration to deliver drugs to the brain via the olfactory and trigeminal nerve pathways (91). Indeed, intranasal administration of antidiabetic peptides has been demonstrated to allow drug delivery directly to the brain in animals (92) and humans (93), with a view to therapeutic application in Alzheimer's disease (94).
There may be other routes by which desmopressin could exert CNS effects, for example by acting from the periphery to alter gene expression in the brain (95), binding to receptors in the periphery that feed back to the CNS, altering permeability of the blood-brain barrier to other substances (96,97), or by the formation of active fragments that can cross the blood-brain barrier following peripheral administration (98-101). In support of the ability of desmopressin to affect brain function, an inhibitory effect of intravenous desmopressin on hypothalamic dopamine function in humans has been reported (102)-it was unclear whether this was a direct or indirect effect.
Studies of desmopressin in the CNS. A systematic literature search was performed to identify studies that investigated effects of desmopressin on the CNS in humans. Forty-one were identified, and 16 were obtained as full-text articles. Details of these are presented in the comprehensive table in supplementary Table SIII. A small number of additional studies of interest were identified through review of abstracts, citation chasing or more focused literature searches-these are also included in Table VI which provides a brief overview of 23 studies.
All studies had relatively small sample sizes.
Desmopressin was administered intranasally in all studies except two that used intramuscular injection in schizophrenia (103,104). In general, studies with intranasal desmopressin used doses ranging from 20-60 µg/day, although there were some outside this range.
Variable effects of desmopressin on different aspects of CNS function were reported. In Table VI, studies are grouped according to outcome of interest: learning, memory, memory after electro-convulsive therapy (ECT), reaction time, language, cognitive function/affective disorder and schizophrenia. Overall, 14 studies showed a clear benefit of desmopressin for some or all of the chosen endpoints (Table VI), while a further three showed unclear or inconsistent benefit. Memory improvements were seen more often in short-term rather than long-term memory.
Summary: oral desmopressin in the CNS. Further basic research is needed in this area before any conclusions can be drawn regarding effects of desmopressin on the CNS. Although a number of studies suggest effects of desmopressin in areas such as learning, memory or clinical symptoms in certain patient populations, studies are often small and of low quality. Furthermore, there are several outstanding questions regarding the overall concept of using desmopressin to target the CNS. These relate primarily to two major issues: the ability of desmopressin to penetrate the blood-brain barrier or act on the CNS from the periphery, and the localisation of desmopressin-responsive receptors in the brain. Given that studies of CNS effects to date have used the intranasal formulation of desmopressin-a delivery mode which is believed to be able to bypass the blood-brain barrier in certain cases-the extrapolation of findings from these studies to oral desmopressin cannot be made without further studies specifically of oral formulations.
Desmopressin in oncology
Vasopressin receptors are present in some cancer cells, including human lung, breast, pancreatic, colorectal, and gastrointestinal tumours (105). It has been suggested that V1 receptors are associated with cellular proliferation, but that the V2 receptor is associated with anti-proliferative effects (106). Desmopressin, as a selective agonist for the V2 receptor, shows anti-tumour properties in breast, colorectal, lung and prostate cancer models (105).
Mechanisms of action/early results
Stimulation of vascular V2 receptors leads to acute release of haemostatic factors into the bloodstream, including Factor VIII, tissue-type plasminogen activator and von Willebrand factor (VWF) (107). VWF is involved in several biological processes such as coagulation (as discussed above), vascular normalisation, cancer cell apoptosis and metastatic resistance. Animal models suggest that efficacy of docetaxel in castration-resistant prostate cancer is enhanced when used in combination with desmopressin (108). Phase II trials in humans also show some encouraging results with the use of desmopressin, including a drop in circulating tumour cells in breast cancer patients (109) and a reduction in tumour vascular perfusion in rectal cancer patients with bleeding (110). In animal studies, infusion of desmopressin during surgery appears to inhibit perioperative metastatic events and may impede micro-metastases that occurred before surgery (109,111).
However, high doses of desmopressin have been used in human trials of desmopressin for cancer treatment: two 1 µg/kg intravenous doses (one just before surgery, one 24 h after surgery) in one study (109) and a maximum tolerated dose of 2x0.5 µg/kg/12 h in another (110).
The likelihood of the oral formulations of desmopressin providing adequate dosing for use in oncological treatment is therefore low. As such, we did not perform an extensive review of the literature on this topic, and intend to carry out a comprehensive review of the use of desmopressin (all formulations) in this therapeutic area as a separate exercise.
4. Conclusion
The use of desmopressin has been explored in a multitude of diverse areas since it was first synthesised (1). Since many of these have not been formally investigated for the purpose of regulatory approval, further studies and RCTs will be needed before any new indications can be recommended. Renal colic is perhaps one of the most promising areas with viable mechanism(s) of action and a reasonably supportive literature on desmopressin use. More studies are required to confirm benefits with oral formulations of desmopressin at standard doses, in monotherapy or combination therapy. Doses at the higher end of the normal range have yielded the most promising results, but dose-finding studies are needed, and the ideal protocol and management of up-titration are yet to be determined.
In bleeding control, most studies of desmopressin that were identified used the intravenous formulation at high doses that are unlikely to be achieved with oral formulations. In cardiac and renal surgery, results are inconsistent but the use of oral desmopressin as a preventative measure before endoscopic sinus surgery or rhinoplasty may be feasible-however, the relevance of intranasal vs oral administration must be investigated. Desmopressin has established efficacy in bleeding disorders but high doses (0.15-0.3 µg/kg IV) are required. Achieving this level of dosing with oral formulations would be challenging.
Further basic research is needed in the CNS (e.g. location of desmopressin-responsive receptors, relevance of blood-brain barrier) before viable uses for oral desmopressin can be properly explored.
Desmopressin has demonstrated intriguing anti-cancer effects in a number of studies, many of which are animal/preclinical. In the small number of human trials, however, high doses of desmopressin have been used (0.5-1 µg/kg IV), again meaning that use of oral formulations is unlikely to be practical.
There are other areas of research that are in their infancy, that may yet prove to be important avenues of investigation for oral forms of desmopressin, such as the bladder and bladder contractility (112), patients with spinal cord injury, and older adults with renal impairment. These are not discussed in this manuscript as there are not yet sufficient studies to gauge the potential role of desmopressin. However, the very fact that we are continuing to learn about credible uses of a drug that was first developed over 50 years ago is testament to the complexity of the human body and the untold possibilities of established, as well as novel, medicines.
Supplementary Material
Bleeding control studies
Renal colic studies.
CNS studies.
Acknowledgements
The authors would like to thank Dr Caroline Loat for providing medical writing support.
Funding
Funding: Medical writing was supported by The Dr Frederik Paulsen Chair at Ghent University, sponsored by Ferring Pharmaceuticals (grant no. A20/TT/1014).
Availability of data and materials
Not applicable.
Authors' contributions
KE, THL, GBK, SR, JPW, JVW, AEK, LD, FH, AFS, JPN and KVJ conceived and designed the study. THL performed the literature searches. KE, THL, KVJ and JPN interpreted the data and drafted the manuscript. Data authentication is not applicable. All authors critically reviewed the manuscript, and have read and approved the final version of the manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
KE has received grants and honoraria to his institution from Ferring, Medtronic, Astellas and Idorsia. THL has worked as a consultant for Ferring Pharmaceuticals. JVW has participated in advisory boards and safety boards and has received speaker fees from Alexion, Ferring, Astellas and Alnylam. FH has received speaker fees from Astellas. JPN is a former full-time employee of Ferring Pharmaceuticals. KVJ is a full-time employee of Ferring Pharmaceuticals. The other authors declare that they have no competing interests.
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