DDAVP

Vasopressin (Rtressin Synthetic) and its derivatives, namely lypressin (Diapid) and desmopressin (DDAVP), regulate the reabsorption of water by the kidneys. Vasopressin is secreted by the pituitary when body fluids must be conserved. An example of this mechanism may be seen when an individual has severe vomiting and diarrhea with little or no fluid intake. When this and similar conditions are present, die posterior pituitary releases the hormone vasopressin, water in die kidneys is reabsorbed into die blood (ie, conserved), and die urine becomes concentrated. Vasopressin exhibits its greatest activity on die renal tubular epithelium, where it promotes water resoqition and smooth muscle contraction throughout die vascular bed. Vasopressin has some vasopressor activity. 

DDAVP (Ferring) Minirin (Ferring) Desmopressin (Kyowa Hakko)... 

Desmopressin (DDAVP) increases the release of factor VIII (von Willebrand factor) from endothelial tissue in the vessel wall. Bleeding time is promptly reduced, within 1 hour of administration, and is sustained for 4 to 8 hours.42 Doses used for uremic bleeding are 0.3 to 0.4 mcg/kg intravenously over 20 to 30 minutes, 0.3 mcg/kg subcutaneously, or 2 to 3 mcg/kg intranasally. Repeated doses can cause tachyphylaxis by... 

FIGURE 50-1. Preliminary (unvalidated) enuresis protocol proposed by the International Children s Continence Society (2004). DDAVP, desmopressin. 

Primary therapy is based on disease severity and type of hemorrhage.7 Most patients with mild to moderate disease and a minor bleeding episode can be treated with l-desamino-8-D-arginine vasopressin [desmopressin acetate (DDAVP)], a synthetic analog of the antidiuretic hormone vasopressin. DDAVP causes release of von Willebrand factor (vWF) and factor VIII from endogenous storage sites. This formulation increases plasma factor VIII levels by three- to fivefold within 30 minutes. The recommended dose is 0.3 mcg/kg intravenously (in 50 mL normal saline infused over 15 to 30 minutes) or subcutaneously or 300 meg intranasally via concentrated nasal spray every 12 hours. Peak effect with intranasal administration occurs 60 to 90 minutes after administration, which is somewhat later than with intravenous administration. Desmopressin infusion may be administered daily for up to 2 to 3 days. Tachyphylaxis, an attenuated response with repeated administration, may occur after several doses.8... 

Most patients with type 1 vWD (functionally normal vWF) and a minor bleeding episode can be treated successfully with desmopressin, which induces secretion of autologous factor VIII and vWF into plasma. The recommended dose is the same as that used to treat mild factor VIII deficiency (0.3 mcg/kg intravenously in 50 mL of normal saline infused over 15 to 30 minutes). This therapy generally is ineffective in type 2A patients who secrete qualitatively abnormal vWF and is controversial in type 2B patients because it may increase the risk of postinfusion thrombocytopenia. Type 3 vWD patients who lack releasable stores of vWF do not respond to DDAVP therapy.18... 

The individual responsiveness to desmopressin is consistent, and a test dose administered at the time of diagnosis or prior to therapy is the best predictor of response. Generally, DDAVP is more effective in vWD than in hemophilia patients, with an average 30% to 50% increase in vWF and factor VIII levels. In patients with an adequate response, desmopressin is first-line therapy because it allows for once-daily administration (elevates plasma levels for 8-10 hours), does not pose a threat in terms of viral transmission, and the cost is substantially less than that of the plasma-derived products. Fibrinolysis inhibitors (50-60 mg/kg of aminocapriotic acid every 4—6 hours or trenex-amic acid 10-15 mg/kg every 8-12 hours) and OCs are used successfully in the management of epistaxis and menorrhagia or as adjuvant treatments. 

Lecithin (t g. DOPC) Desmopressin (dDAVP) Renin inhibitor (11214/03) Lypressin (LVP) Somatostatin (SRIF)... 

In vivo Release of Desmopressin and Somatostatin. The in vivo release of Desmopressin and Somatostatin after subcutaneous and intramuscular injections of the peptide in the cubic or the lamellar phase has been studied in the rabbit. Blood was sampled at regular intervals, and systemically absorbed Desmopressin and Somatostatin were determined as the specific immunoreactitvity in plasma of the actual peptide. For details of the analyses with dDAVP, consult ref. 9. For comparison, Desmopressin-like and Somatostatin-like immunoreactitvity (dDAVP-LI and SRIF-LI) in plasma after intravenous bolus injections of the two peptides were determined as well. 

Figure 2. Spin-echo -NMR spectra from a diffusion experiment with a cubic phase of dDAVP (10%), MO (60%) and 2H20 (40%). Temperature 40 C, t=20 ms, A=24 ms, g=l 19 gauss/cm and 8=1.0,2.0..., 9.0 ms. The inset shows the aromatic region originating from dDAV P at a higher amplification. Also shown is the pulse sequence used in the NMR-diffusion method (see text for details).

Figure 3. In vitro release experiments for dDAVP and LVP in various cubic phases at 37 C. The compositions of the samples are listed in Table n.

Desmopressin. Desmopressin is an analogue to the endogenous antidiuretic peptide hormone Vasopressin in which the modifications of the N-terminous amino acid and the replacement of the L-Arg for a D-Arg in position 8, significantly increases its biological stability. In this investigation, the half-life of dDAVP in the rabbit after intravenous administration was determined to be approximately 45 minutes. 

The dDAVP preparations used in this study were prepared in low water contents so that the lamellar phase was formed, which in turn was injected into the rabbits. The reason for this was the fact that the lamellar phase with its mucous-like rheology is easier to inject than the stiff cubic phase. Since the lamellar phase swells into the cubic phase in excess water according to the phase diagram in Figure 1, a phase transition was expected also in the in vivo situation. The transition was found to be very fast as judged by inspection of the injection site immediately after administration. 

As can be seen in Figure 4a, incorporation of dDAVP in the liquid crystalline phase significantly prolongs the apparent half-life of the peptide. No decline in plasma dDAVP-LI was found during the observation period of five hours, and the level of dDAVP-LI in plasma thus seems to correlate with an apparent zero-order release process of dDAVP. No difference in plasma dDAVP-LI could be found between sc and im administration. 

The inclusion of Somatostatin into a cubic phase markedly prolonged the apparent half-life. As can be seen in Figure 4b, the plasma level of Somatostatin-like immunoreactivity (SRIF-LI) after sc administration of cubic preparations of SRIF was nearly constant during the observation time of six hours, and no decline in the plasma level could be seen. During this period, the level of SRIF-LI in plasma thus seems to correlate with a zero-order release process of SRIF (cf. dDAVP). In Figure 4b is also shown the plasma SRIF-LI after sc administration of the peptide solubilized in cubic phases with varying ratios of MO/LE. It can be seen that increasing the amount of LE... 

---