Percutaneous Penetration Kinetics of Nitroglycerin and Its Dinitrate Metabolites Across Hairless Mouse Skin in Vitro

The percutaneous penetration kinetics of the antianginal, nitroglycerin (GTN), and its primary metabolites, 1,2- and 1,3-glyceryl dinitrate (1,2- and 1,3-GDN), were evaluated in vitro, using full-thickness hairless mouse skin. GTN and the 1,2- and 1,3-GDNs were applied (a) in aqueous solution as pH 7.4 phosphate-buffered saline (PBS) and (b) incorporated into lipophilic ointment formulations. The cutaneous transformation of GTN to its dinitrate metabolites was detected, but no interconversion between 1,2-GDN and 1,3-GDN was observed. Following application of the nitrates in PBS solution, all three compounds exhibited steady-state transport kinetics. The steady-state flux of GTN (8.9 ± 1.5 nmol cm^–2 hr^–1) was significantly greater (P < 0.05) than those of 1,2-GDN (0.81 ± 0.54 nmol cm^–2 hr^–1) and 1,3-GDN (0.72 ± 0.20 nmol cm^–2 hr^–1). The corresponding permeability coefficient () for GTN (20 ± 3 × 10^–3 cm hr^–1) was significantly larger than the corresponding values for 1,2-GDN (1.4 ± 0.9 × 10^–3 cm hr^–1) and 1,3-GDN (1.2 ± 0.4 × 10^–3 cm hr^–1), which were statistically indistinguishable (P > 0.05). Further analysis of the transport data showed that the differences between GTN and the GDNs could be explained by the relative stratum corneum/water partition coefficient (K _s) values of the compounds. The apparent partition parameters, defined as = K _s · h [where h is the diffusion path length through stratum corneum (SC)] were 19.8 ± 2.5 × 10^–2 cm for GTN and 1.91 ± 1.07 × 10^–2 and 1.81 ± 0.91 × 10^–2 cm for 1,2- and 1,3-GDN, respectively. However, when the nitrates were administered in an ointment base, the apparent partition parameter (') and permeability coefficient (') of GTN markedly decreased, to 2.51 ± 0.75 × 10^–2 cm and 1.6 ± 0.3 × 10^–3 cm hr^–1, respectively. In contrast, the ' and ' results for 1,2- and 1,3-GDN were not significantly different (P > 0.05) from the corresponding and values, which were measured following dosing as aqueous solutions. As a result, the steady-state fluxes of all three nitrates from the ointment formulation were comparable (GTN, 154 ± 28 nmol cm^–2 hr^–1; 1,2-GDN, 162 ± 22 nmol cm^–2 hr^–1; 1,3-GDN, 162 ± 34 nmol cm^–2 hr^–1). It follows that the dinitrates can be as efficiently delivered across the skin as GTN when a suitable formulation is employed. This finding may support transdermal therapy using 1,2- or 1,3-GDN if, indeed, they are found to be pharmacologically effective.     

硝酸甘油贴剂(心泰膏)透皮吸收示踪研究

本文用放射性同位素示踪技术,以体外和体内两种方法测定了硝酸甘油贴剂(心泰膏Nitrogum)中硝酸甘油的透皮吸收速率。体内法测定结果表明,小鼠在24h内每小时的透皮吸收平均速率为10.5μg/cm~2。不同种属的动物皮肤,经体外测定,每小时平均渗透速率(μg/cm~2)如下:10.4(小鼠)、9.5(大鼠)、8.6(豚鼠)和8.7(人皮)。说明不同种动物其皮肤渗透速率是不同的。在实验测定时间内,各种皮肤的渗透累积量与时间成正比,表明硝酸甘油恒速渗透。     

Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve

Summary The time course and the magnitude of the effect of glyceryl trinitrate (GTN) on central venous (pulmonary artery diastolic pressure-PAP_d) and peripheral arterial (a/b-ratio of the finger pulse wave) haemodynamics were compared in a randomized double-blind cross-over study in 12 patients suffering from congestive heart failure (NYHA II–III) with elevated PAD_d at rest (15 mm Hg). The data were obtained in a bioavailability study of two sprays of glyceryl trinitrate, which differed in their galenical characteristics and in the dose of GTN (0.4 mg vs. 0.8 mg). Following sublingual administration of each spray, PAP_d, a/b-ratio and the plasma concentrations of GTN and its metabolites were measured up to 30 min.The relative bioavailability of GTN of the test preparation was estimated to be 157%, 161% and 147%, when calculated from the plasma concentration-time data or the integrated effect of GTN on a/b-ratio or PAP_d, respectively. The mean time courses of the decrease in PAP_d and the increase in the a/b-ratio of the finger pulse curve were mirror images. Thus, there was a strong correlation between the mean values of PAP_d and a/b-ratio following the administration of glyceryl trinitrate. Since the slope of the relationship differed considerably between the patients, the magnitude of effect of GTN on PAP_d in the individual patient could not be predicted from the changes in a/b-ratio.     

Rectogesic® (glyceryl trinitrate 0.2%) ointment relieves symptoms of haemorrhoids associated with high resting anal canal pressures

OBJECTIVE: Some haemorrhoids are associated with high resting anal canal pressures. The aim of this study was to assess if Rectogesic, a topical glyceryl trinitrate 0.2% ointment was effective in relieving symptoms of early grade haemorrhoids associated with high resting anal canal pressures. METHOD: This was a prospective, two-centre, open label study of 58 patients with persistent haemorrhoidal symptoms. Patients with first or second degree haemorrhoids and a maximum resting anal canal pressure > 70 mmHg were included. Rectogesic was applied three times a day for 14 days. Anorectal manometry was performed 30 min after the first application of Rectogesic. A 28-day diary was completed during 14 days of therapy and for 14 days after cessation of treatment. This recorded the incidence of rectal bleeding, and visual analogue scales for anal pain, throbbing, pruritis, irritation and difficulty in bowel movement. RESULTS: Maximum resting anal canal pressures were reduced after application of Rectogesic (115.0 +/- 40.4 mmHg vs 94.7 +/- 34.1 mmHg, P < 0.001). In the study period and at 14 days after cessation of Rectogesic, there was significant reduction in rectal bleeding (P = 0.0002), and significant improvement of anal pain (P = 0.0024), throbbing (P = 0.0355), pruritis (P = 0.0043), irritation (P = 0.0000) and difficulty in bowel movement (P = 0.001). The main adverse event was headache in 43.1% of patients. CONCLUSION: Rectogesic is a safe and feasible treatment for patients with early grade haemorrhoids associated with high resting anal canal pressures.     

Topical 0.2 percent glyceryl trinitrate ointment has a short-lived effect on resting anal pressure

PURPOSE: Glyceryl trinitrate ointment applied to the anal verge lowers anal resting pressure, but its duration of action is uncertain. This study investigated the effect and duration of action of 0.2 percent glyceryl trinitrate on anal resting pressure and hemodynamic parameters. METHODS: A total of 15 volunteers, 9 male, with a median age of 30 (range, 20–71) years, underwent continuous static anal manometry using a solid state catheter for ten minutes before and two hours after applying 0.2 percent glyceryl trinitrate ointment to the anoderm with a gloved finger. Pulse and blood pressure were recorded every 15 minutes. RESULTS: A significant reduction in maximal anal resting pressure compared with preglyceryl trinitrate values was observed at 15, 30, 45, 60, and 90 minutes after application, but no significant difference thereafter. There was no significant change in pulse during the study. Systolic and diastolic blood pressures dropped significantly after application of glyceryl trinitrate, but had recovered and were not significantly different from original values after 90 minutes. A significant fall in blood pressure did not correlate with the onset or duration of side effects. CONCLUSIONS: Continuous static manometry (as opposed to interval measurements reported in previous studies) demonstrates that 0.2 percent glyceryl trinitrate ointment significantly lowers anal resting pressure, but only for 90 minutes. Twice daily application of topical 0.2 percent glyceryl trinitrate heals two-thirds of fissures after eight weeks, but its apparently short duration of action may indicate that more frequent application might heal more fissures, more rapidly.Supported by a Royal College of Surgeons of England Research Fellowship, Lincoln's Inn Fields, London WC2A 3PN, United Kingdom.Presented at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, June 24 to 29, 2000.     

Nitric oxide: novel therapy for osteoporosis

Background: Relative nitric oxide (NO) deficiency is responsible for many pathophysiological processes, including in postmenopausal women providing a plausible biological basis for use of NO replacement therapy in humans. Excess or inappropriate local production of NO aggravates bone destruction in some diseases such as septic shock, rheumatoid and other inflammatory arthropathies. Results: A variety of in vitro and in vivo data have revealed the efficacy of nitroglycerin and nitrates on bone cells. Since some part of the beneficial effects of estrogen on bone is mediated via the NO–cGMP pathway, NO donor therapy is an attractive alternative to estrogen therapy to prevent and treat osteoporosis. When the body cannot generate adequate amounts of NO for biological homeostasis, administration of exogenous NO or prolongation of the actions of endogenous NO are practical ways to supplement NO, especially in postmenopausal women. Conclusion: Postmenopausal NO deficiency is rectified with hormone replacement therapy, which enhances local production of NO. Declining local NO production secondary to estrogen deficiency in postmenopausal women, and perhaps in older men, could be one of the key reasons for age-related increased incidences of cardiovascular events, sexual dysfunction as well as osteoporosis. Thus, in addition to supplementation of NO compounds in acute situations such as alleviating angina and erectile dysfunction, it could be a valuable addition to the armamentarium of therapies for chronic conditions such as osteoporosis.     

Asynchronous segmental early relaxation of the left ventricle

Asynchronous left ventricular segmental early relaxation (SER) is an angiographic finding with unclear pathophysiological mechanism. We analyzed 158 consecutive, technically adequate left ventricular cineangiograms of patients undergoing diagnostic cardiac catheterization. Patients with valvular disease, cardiomyopathy, or borderline coronary artery disease (50-74% lumen diameter reduction) were excluded. The patients were divided according to the presence or absence of coronary artery disease, segmental early relaxation, and left ventricular asynergy. Significant coronary artery disease was detected in 127 patients (80%), segmental early relaxation in 63 (40%), and asynergy in 85 (54%). Forty-five percent of patients with unobstructed arteries and 38% with significant coronary artery disease exhibited segmental early relaxation. Twenty-nine percent of patients with coronary artery disease and no asynergy, had segmental early relaxation, while this phenomenon was present in patients with coronary artery disease and asynergy. Since coronary artery disease subgroups are difficult to compare in terms of left ventricular mechanics, two groups of normal patients, 15 with and 14 without segmental early relaxation, were further evaluated: Left ventricular pressure, heart rate, dPdT, left ventricular diastolic volume and wall thickness were not significantly different. Left ventricular end-systolic volume index was 30.3 ± 4.6 ml/m² in patients with segmental early relaxation and 22.5 ± 5.1 ml/m² in those without segmental early relaxation (p < 0.01), while peak wall stress was 332.4 ± 66.6 dynes/cm² × 10³ and 272.2 ± 47.1 dynes/cm² × 10³, respectively (p < 0.02). A third group of patients with segmental early relaxation and coronary artery disease had a repeat left ventricular angiogram after nitroglycerin: Segmental early relaxation disappeared in 12 (group A) and persisted in 4 (group B). After nitroglycerin, end-systolic volume index decreased by 22% ± 8% in group A and by 1% ± 8% in group B (p < 0.005), while wall stress decreased by 24% ± 12% in group A and did not change in group B (p < 0.01). We conclude that segmental early relaxation, is (1) a very common finding (40% of the entire group); (2) frequent among normals (48%); (3) not a reliable predictor of coronary artery disease; (4) appears to be directly related to end-systolic volume index and wall stress; (5) disappears following nitroglycerin when this drug decreases end-systolic volume index and wall stress.     

Effects of nitric oxide donors on vascular smooth muscles depend on a type of vascular smooth-muscle preactivation

The abilities of such therapeutic nitrovasodilators as sodium nitroprusside (SNP) and glyceryl trinitrate (GTN) to dilate vascular smooth muscles (VSM) and affect intracellular calcium concentration level ([Ca²⁺]_i) in a rat tail artery were tested under different types of preactivation. To shed light on mechanisms underlying possible differences in the action of these two nitric oxide (NO) donors, simultaneous measurements of [Ca²⁺]_i and contractile force were done. All vascular rings were precontracted either using a high-K⁺-Krebs solution or phenylephrine (PE). It was shown that the effect of both NO donors strongly depended on a type of VSM preactivation. The EC₅₀ for GTN under K⁺ stimulation of VSM comprised (2.48±1.6)×10⁻⁵ M, whereas the mean EC₅₀ under PE stimulation was (3.05±2.3)×10⁻⁴ M (p<0.05, n=9). The EC₅₀ for SNP under K⁺ stimulation of VSM comprised (1.09±0.47)×10⁻⁷ M, whereas the EC₅₀ under PE stimulation was (8.01±2.4)×10⁻⁶ M (p<0.05, n=9). GTN demonstrated a significant discrepancy in the magnitude of changes in [Ca²⁺]_i and related VSM relaxant responses, indicating the ability of GTN to relax VSM in the absence of a proportional decrease in [Ca²⁺]_i. The main peculiarity of SNP action under K⁺ stimulation as compared to PE stimulation was the transient decrease in [Ca²⁺]_i while relaxation was sustained. Therefore, both NO donors demonstrated their ability to produce vasorelaxation as a result of an alteration in myofilament calcium sensitivity. These data clearly indicate that the sensitivity of VSM to NO donors is higher under K⁺ depolarization than that seen under PE stimulation, indicating that Ca²⁺ entry through voltage-operated calcium channels is more sensitive to NO as compared to calcium mobilization by means of Ca²⁺ entry through receptor-operated calcium channels or intracellular Ca²⁺ release, or both.     

Effect of the nitric oxide donor, glyceryl trinitrate, on human gall bladder motility

Background—Nitric oxide is a majorneurotransmitter in non-adrenergic, non-cholinergic (NANC) pathways.NANC inhibitory innervation has been shown in human gall bladder musclein vitro; the role of nitric oxide in human gall bladder emptyinghowever is undefined.
Aims—To study the effect of glyceryltrinitrate, a nitric oxide donor, on gall bladder emptying in healthysubjects using a randomised, double blind, crossover, placebocontrolled design.
Methods—Ultrasonographic gall bladdervolume was measured in the fasting state in eight healthy volunteersafter randomised administration of either glyceryl trinitrate 1200 µgbuccal spray or placebo spray. On two further occasions, afterrandomised administration of either glyceryl trinitrate 1200 µgbuccal spray or placebo spray, gall bladder volumes were also measuredafter a liquid test meal.
Results—Glyceryl trinitrate significantlyincreased fasting gall bladder volume to a mean of 114% (SEM 5%) ofpretreatment volume (p=0.039). Glyceryl trinitrate also significantlyimpaired gall bladder emptying between five and 40 minutespostprandially. Gall bladder ejection fraction was also reduced afterglyceryl trinitrate compared with placebo (43 (6.9)% versus 68.4 (6.5)%, p=0.016).
Conclusions—This study shows that glyceryltrinitrate produces gall bladder dilatation in the fasting state andreduces postprandial gall bladder emptying, suggesting that nitricoxide mechanisms may be operative in the human gall bladder in vivo.

Keywords:gall bladder motility; nitric oxide; glyceryltrinitrate

     

Innovations in chronic anal fissure treatment: A systematic review

A chronic anal fissure is a common perianal condition. This review aims to evaluate both existing and new therapies in the treatment of chronic fissures. Pharmacological therapies such as glyceryl trinitrate (GTN), Diltiazem ointment and Botulinum toxin provide a relatively non-invasive option, but with higher recurrence rates. Lateral sphincterotomy remains the gold standard for treatment. Anal dilatation has no role in treatment. New therapies include perineal support devices, Gonyautoxin injection, fissurectomy, fissurotomy, sphincterolysis, and flap procedures. Further research is required comparing these new therapies with existing established therapies. This paper recommends initial pharmacological therapy with GTN or Diltiazem ointment with Botulinum toxin as a possible second line pharmacological therapy. Perineal support may offer a new dimension in improving healing rates. Lateral sphincterotomy should be offered if pharmacological therapy fails. New therapies are not suitable as first line treatments, though they can be considered if conventional treatment fails.