Felypressin (PLV-2)

Injectable local anaesthetic agents for dental anaesthesia

Background: Pain during dental treatment, which is a common fear of patients, can be controlled successfully by local anaesthetic. Several different local anaesthetic formulations and techniques are available to dentists. Objectives: Our primary objectives were to compare the success of anaesthesia, the speed of onset and duration of anaesthesia, and systemic and local adverse effects amongst different local anaesthetic formulations for dental anaesthesia. We define success of anaesthesia as absence of pain during a dental procedure, or a negative response to electric pulp testing or other simulated scenario tests. We define dental anaesthesia as anaesthesia given at the time of any dental intervention.Our secondary objective was to report on patients' experience of the procedures carried out. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2018, Issue 1), MEDLINE (OVID SP), Embase, CINAHL PLUS, WEB OF SCIENCE, and other resources up to 31 January 2018. Other resources included trial registries, handsearched journals, conference proceedings, bibliographies/reference lists, and unpublished research. Selection criteria: We included randomized controlled trials (RCTs) testing different formulations of local anaesthetic used for clinical procedures or simulated scenarios. Studies could apply a parallel or cross-over design. Data collection and analysis: We used standard Cochrane methodological approaches for data collection and analysis. Main results: We included 123 studies (19,223 participants) in the review. We pooled data from 68 studies (6615 participants) for meta-analysis, yielding 23 comparisons of local anaesthetic and 57 outcomes with 14 different formulations. Only 10 outcomes from eight comparisons involved clinical testing.We assessed the included studies as having low risk of bias in most domains. Seventy-three studies had at least one domain with unclear risk of bias. Fifteen studies had at least one domain with high risk of bias due to inadequate sequence generation, allocation concealment, masking of local anaesthetic cartridges for administrators or outcome assessors, or participant dropout or exclusion.We reported results for the eight most important comparisons.Success of anaesthesiaWhen the success of anaesthesia in posterior teeth with irreversible pulpitis requiring root canal treatment is tested, 4% articaine, 1:100,000 epinephrine, may be superior to 2% lidocaine, 1:100,000 epinephrine (31% with 2% lidocaine vs 49% with 4% articaine; risk ratio (RR) 1.60, 95% confidence interval (CI) 1.10 to 2.32; 4 parallel studies; 203 participants; low-quality evidence).When the success of anaesthesia for teeth/dental tissues requiring surgical procedures and surgical procedures/periodontal treatment, respectively, was tested, 3% prilocaine, 0.03 IU felypressin (66% with 3% prilocaine vs 76% with 2% lidocaine; RR 0.86, 95% CI 0.79 to 0.95; 2 parallel studies; 907 participants; moderate-quality evidence), and 4% prilocaine plain (71% with 4% prilocaine vs 83% with 2% lidocaine; RR 0.86, 95% CI 0.75 to 0.99; 2 parallel studies; 228 participants; low-quality evidence) were inferior to 2% lidocaine, 1:100,000 epinephrine.Comparative effects of 4% articaine, 1:100,000 epinephrine and 4% articaine, 1:200,000 epinephrine on success of anaesthesia for teeth/dental tissues requiring surgical procedures are uncertain (RR 0.85, 95% CI 0.71 to 1.02; 3 parallel studies; 930 participants; very low-quality evidence).Comparative effects of 0.5% bupivacaine, 1:200,000 epinephrine and both 4% articaine, 1:200,000 epinephrine (odds ratio (OR) 0.87, 95% CI 0.27 to 2.83; 2 cross-over studies; 37 participants; low-quality evidence) and 2% lidocaine, 1:100,000 epinephrine (OR 0.58, 95% CI 0.07 to 5.12; 2 cross-over studies; 31 participants; low-quality evidence) on success of anaesthesia for teeth requiring extraction are uncertain.Comparative effects of 2% mepivacaine, 1:100,000 epinephrine and both 4% articaine, 1:100,000 epinephrine (OR 3.82, 95% CI 0.61 to 23.82; 1 parallel and 1 cross-over study; 110 participants; low-quality evidence) and 2% lidocaine, 1:100,000 epinephrine (RR 1.16, 95% CI 0.25 to 5.45; 2 parallel studies; 68 participants; low-quality evidence) on success of anaesthesia for teeth requiring extraction and teeth with irreversible pulpitis requiring endodontic access and instrumentation, respectively, are uncertain.For remaining outcomes, assessing success of dental local anaesthesia via meta-analyses was not possible.Onset and duration of anaesthesiaFor comparisons assessing onset and duration, no clinical studies met our outcome definitions.Adverse effects (continuous pain measured on 170-mm Heft-Parker visual analogue scale (VAS))Differences in post-injection pain between 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine are small, as measured on a VAS (mean difference (MD) 4.74 mm, 95% CI -1.98 to 11.46 mm; 3 cross-over studies; 314 interventions; moderate-quality evidence). Lidocaine probably resulted in slightly less post-injection pain than articaine (MD 6.41 mm, 95% CI 1.01 to 11.80 mm; 3 cross-over studies; 309 interventions; moderate-quality evidence) on the same VAS.For remaining comparisons assessing local and systemic adverse effects, meta-analyses were not possible. Other adverse effects were rare and minor.Patients' experiencePatients' experience of procedures was not assessed owing to lack of data. Authors' conclusions: For success (absence of pain), low-quality evidence suggests that 4% articaine, 1:100,000 epinephrine was superior to 2% lidocaine, 1:100,000 epinephrine for root treating of posterior teeth with irreversible pulpitis, and 2% lidocaine, 1:100,000 epinephrine was superior to 4% prilocaine plain when surgical procedures/periodontal treatment was provided. Moderate-quality evidence shows that 2% lidocaine, 1:100,000 epinephrine was superior to 3% prilocaine, 0.03 IU felypressin when surgical procedures were performed.Adverse events were rare. Moderate-quality evidence shows no difference in pain on injection when 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine were compared, although lidocaine resulted in slightly less pain following injection.Many outcomes tested our primary objectives in simulated scenarios, although clinical alternatives may not be possible.Further studies are needed to increase the strength of the evidence. These studies should be clearly reported, have low risk of bias with adequate sample size, and provide data in a format that will allow meta-analysis. Once assessed, results of the 34 'Studies awaiting classification (full text unavailable)' may alter the conclusions of the review.

Effects of vasoconstrictors used in local anesthesia upon isolated rat heart

Some reports have demonstrated that the vasoconstrictor effect of catecholamines may be amplified by felypressin. Thus, the association of felypressin and epinephrine with local anesthetics may be indicated to achieve more effective vasoconstrictor actions with fewer collateral effects from both the anesthetic and the vasoconstrictor. This study aimed to characterize the effects of felypressin and associations of felypressin and epinephrine upon the contraction force and the cardiac rate of the isolated rat heart (n=20) perfused by Langendorff's method. The following solutions were utilized: epinephrine, 4.5nmol; felypressin at doses of 0.5, 1.6 and 5.5IU and associations of felypressin at the same doses with 4.5nmol epinephrine. Contraction force and cardiac rate were recorded at 15, 30, 60 and 120s after the administration of each solution, and before the administration, a control measurement (time 0) was taken. Felypressin at a dose of 0.5IU did not have any effect upon the heart, but the doses of 1.6 and 5.5IU decreases the cardiac rate and the contraction force, respectively. Epinephrine and all of the felypressin and epinephrine associations produced increases in these parameters. The association of 0.5IU felypressin and 4.5nmol epinephrine promoted a similar effect to that of epinephrine (4.5nmol) alone up to 120s. The association of 1.6IU felypressin and 4.5nmol epinephrine increases the contraction force up to 60s. After the administration of the association of 5.5IU felypressin and 4.5nmol epinephrine this increase was observed up to just 30s. The cardiac rate values obtained after the administration of the associations of 1.6 and 5.5IU felypressin with 4.5nmol epinephrine were lower than those seen after the use of 4.5nmol epinephrine alone. In this study it was observed that the association of felypressin with epinephrine decreased the effects of epinephrine which increases the cardiac rate and the contraction force in the isolated rat heart.

Comparison of epinephrine and felypressin pressure effects in 1K1C hypertensive rats treated or not with atenolol

Purpose: Epinephrine is considered the gold standard vasoconstrictor for hypertensive patients, but few studies report felypressin's effects. The present study aimed to analyze and compare the effects of these two vasoconstrictors, injected by the intravenous route, on the arterial pressure of normotensive, hypertensive and atenolol-treated hypertensive rats.
Method: The hypertension model was one-kidney-one-clip (1K1C): the main left renal artery was partially constricted and the right kidney was surgically removed in 45-day-old male Wistar rats. 1K1C hypertensive rats received atenolol (90 mg/kg/day) by gavage for 2 weeks. 28-35 days after hypertension induction, a catheter was inserted into the left carotid artery to record direct blood pressure values. The following parameters were recorded: minimal hypotensive response, maximal hypertensive response, response duration and heart rate.
Results: Epinephrine, but not felypressin, exerted an important hypotensive action; non-treated hypertensive rats showed more pronounced vasodilation. Treated and non-treated rats showed hypertensive responses of the same magnitudes in all groups; 1K1C atenolol rats showed reduced hypertensive responses to both vasoconstrictors. Felypressin's response duration was longer than that of epinephrine in all groups. Epinephrine increased heart rate while felypressin reduced this parameter only in the normotensive group.
Conclusions: Our results suggest that felypressin has equipotent pressure responses when compared with epinephrine, showing a greater extent of action. Atenolol's reduction of hypertensive effects surprisingly suggests that atenolol β-blockade may also be important for felypressin's cardiovascular effect, as is widely known for epinephrine. Our data suggest that felypressin is safe for hypertensive subjects, in particular those receiving atenolol.

Clinically safe dosage of felypressin for patients with essential hypertension

Hemodynamic changes were evaluated in patients with essential hypertension when felypressin of various concentrations was administered. The parameters studied were systolic pressure, diastolic pressure, heart rate, left ventricular systolic phase, and endocardial viability ratio. Results showed that blood pressure tended to increase, and the value of 1/pre-ejection period2 (PEP2) tended to decrease, upon administration of 3 ml of 2% propitocaine containing 0.06 international units/ml (IU/ml) of felypressin. Significant increase of blood pressure and decrease in 1/PEP2 was noted upon administration of 3 ml of anesthetic solution containing 0.13 IU/ml of felypressin. No ischemic change of the myocardium was detected even with the highest felypressin concentration (3 ml of 2% propitocaine containing 0.25 IU/ml of felypressin). These results suggest that the clinically safe dosage of felypressin for patients with essential hypertension is approximately 0.18 IU. This amount is equivalent to 6 ml of 3% propitocaine with 0.03 IU/ml of felypressin, which is a commercially available local anesthetic for dental use. It seems that the decrease in 1/PEP2 that occurred during blood pressure increase was due to the increase in afterload caused by contraction of the arterioles. Although in the present study no ischemic change was noted, special care should be taken to prevent myocardial ischemia in patients with severe hypertension.

Felypressin increases blood pressure during dental procedures in hypertensive patients

Background: Felypressin has been added to local anesthetic to increase the length of the anesthetic effect and reduce toxicity during dental procedures. However, the effect on blood pressure remains uncertain, and this may be highly relevant in the dental treatment of hypertensive patients.
Objective: To investigate the effect of felypressin on blood pressure in hypertensive patients with controlled BP.
Methods: 71 subjects with these characteristics and in need of periodontal treatment were studied. After 10 minutes of rest, local anesthesia (prilocaine) was infiltrated with and without addition of felypressin. Then, a deep subgingival scaling was performed. Blood pressure was measured by an automated oscillometric device (DIXTAL DX2010). Ten minutes after the administration of the anesthetic, peak anesthetic action was recorded. The State-Trait Anxiety Inventory (STAI) was used to assess the patients' trait anxiety.
Results: Systolic blood pressure increased after anesthesia, regardless of association with felypressin, throughout the dental procedure (p<0.05) and this response can be explained, at least in part, by the trait anxiety levels of the subjects. However, a further increase in diastolic blood pressure was observed when prilocaine was associated with felypressin (p<0.05), but this response did not change with trait anxiety levels.
Conclusion: Felypressin increased the diastolic blood pressure of hypertensive patients with controlled blood pressure. Patients with high trait anxiety presented increases in systolic blood pressure upon some procedures, suggesting that an increase in blood pressure might also be related to fear or anxiety.