Pharmacokinetic Characteristics of a Nifedipine and Lidocaine Fixed Combination in the Form of Rectal Cream: Two Decades Data Analysis

The creation of medicines' fixed combinations from compounds with complementary effects is one of the most popular directions in modern pharmacology and pharmaceutics. In case of nifedipine and lidocaine fixed combination such approach is quite obvious. The present review article is devoted to the analysis of clinical and non-clinical studies results on the assessment of the pharmacokinetic characteristics of these medicines. Although the oral route is the most convenient for drug administration, there are a number of circumstances where this is not possible from either a clinical or pharmaceutical perspective. In these cases, the rectal route may represent a practical alternative and can be used to administer drugs for both local and systemic actions. Research data of last decades suggested that nifedipine, a calcium channel blocker, could be effective in reducing anal resting pressure and in healing chronic anal fissure and acute thrombosed hemorrhoids. Another component of fixed combination lidocaine is a local anesthetic usually used to relieve pain of anal fissures and symptomatic hemorrhoids. In combinations lidocaine and nifedipine have complementary actions. Analysis of all available studies (during last 2 decades) which were aimed to investigate pharmacokinetic characteristics of a nifedipine and lidocaine fixed combination in the form of rectal cream showed that following topical application, the active ingredients nifedipine and lidocaine are absorbed into the bloodstream in only small quantities that have no major implications for the safety of the product, and systemic absorption, if any, was incomparably lower than absorption following per os administration of the two active ingredients.

HIGH-RESOLUTION ANORECTAL MANOMETRY IN TESTING ANORECTAL FUNCTION AFTER COMBINATION TREATMENT FOR RECTAL CANCER

The purpose of the study was to evaluate anorectal function with high-resolution anorectal manometry in patients receiving combination treatment for rectal cancer. Material and methods. We analyzed literature data (PubMed, Scopus, eLIBRARY databases) and our treatment outcomes in 50 rectal cancer patients receiving combination or surgical treatment at Rostov Research Institute of Oncology. Results. The mean anal resting pressure was 1.8 times lower, and the maximal anal squeeze pressure was 1.5 times lower in patients after combination treatment, compared to surgical treatment (p<0.05). 3 months after combination treatment with prolonged radiotherapy, contractile properties of the internal sphincter were decreased in 83.3%, of the external sphincter - in 26.7% of patients. Fatigue rate of external sphincter muscles was increased in 17 (56.7%) patients of this group. We observed a correlation between some anorectal manometry data and the LARS score: in both groups, patients with the maximal LARS score showed the lowest mean anal resting pressure, compared to patients with minimal and average LaRs scores (p<0.05). Conclusion. Due to negative effect of radiation therapy on the anorectal function, careful selection of patients who will benefit from radiation therapy is very important, as well as identification of patients with a high risk of radiation-induced functional problems and development of rehabilitation programs for patients treated for rectal cancer.

Oxycodone and macrogol 3350 treatment reduces anal sphincter relaxation compared to combined oxycodone and naloxone tablets

Background Opioid analgesics inhibit anal sphincter function and contribute to opioid-induced bowel dysfunction. However, it is unknown if the inhibition can be reduced by opioid antagonism with oral naloxone, and how this compares to osmotic laxative treatment. Aims To compare the effects of oxycodone and macrogol 3350 treatment (OX + PEG) versus combined oral oxycodone and naloxone (OXN) on anal sphincter function and gastrointestinal symptoms. Methods A randomised, double-blind, crossover trial was conducted in 20 healthy, male volunteers. Participants were randomised to five days treatment of OX + PEG or OXN. Anal resting pressure, anal canal distensibility, and rectoanal inhibitory reflex-induced sphincter relaxation were evaluated at baseline and on day 5. The Patient Assessment of Constipation questionnaire (PAC-SYM), stool frequency, and stool consistency were assed daily. Results Sphincter relaxation was reduced after OX + PEG treatment compared to OXN (difference = −17.6% [95% Cl;−25.2, −10.2]; P < 0.001). Anal resting pressure and anal canal distensibility did not differ between the treatments. PAC-SYM abdominal symptom subscale increased during OX + PEG compared to OXN (cumulated score: 3.2±2.3 vs. 0.2±1.8; P =0.002). Number of bowel movements was higher during OX + PEG vs. OXN (5.4±1.5 vs. 4.2±1.2; P = 0.035), but there was no difference in stool consistency (3.5±0.5 vs. 3.2±0.4; P = 0.14). Conclusions Sphincter relaxation was significantly reduced after OX + PEG compared to OXN. Evaluation of the rectoanal inhibitory reflex may serve as an important objective measure in future trials on treatment of opioid-induced bowel dysfunction.

Role of recto-anal biofeedback in management of fecal incontinence: early experience for prospective non-surgical management

Background: Fecal incontinence is a difficult and debilitating problem with various nonsurgical and surgical modes of treatment. Biofeedback is among the most considerable nonoperative strategies. This study is to review of the short-term effectiveness of the use of biofeedback therapy in management of fecal incontinence.Methods: A retrospective review of 14 patients with fecal incontinence were included and completed the planned biofeedback sessions regarding clinical response and change in anorectal manometric parameters.Results: 14 incontinent patients (9 males and 5 females), mean age 38.0 ± 21.4 years, 6 patients (42.8%) showed excellent response (cured), 5 patients (35.7%) showed good response (improved) and 3 patients (21.5%) showed poor response. There were a highly significant decrease in the grade with mean 3.8±1.4 to 2.4±1.7 (P value =0.003) and a score mean 11.8±5.9 to 6.1±7.1 (P value = 0.002). increase in anal resting pressure by mean 33.6±18.1 mmHg (P value = 0.004) and anal squeeze pressure by mean 75.4±35.2 mmHg (P value = 0.002). Also increase in anal resting pressure from 36.2±13.4 mmHg to 46.0±19.7 mmHg (P value = 0.046) and the anal squeeze pressure 89.3±21.8 mmHg to 106.7±21.0 mmHg (P value = 0.026). the volume required for 1st sensation mean 34.6±10.8 cc. decreased to 29.3±9.4 cc. (P value = 0.048) and the maximum tolerable volume increases from 221.4±55.9 cc to 235.7±54.9 cc (P-value = 0.022).Conclusions: Biofeedback therapy has an effective role in short term efficacy in management of fecal incontinence.

Myoxinol (HydrolyzedHibiscus esculentusExtract) in the Cure of Chronic Anal Fissure: Early Clinical and Functional Outcomes

Objective.This study was designed to evaluate the early results of the topical application of HydrolyzedHibiscus esculentusExtract 3% ointment (Myoxinol 3%), a novel local product with Botox-like activity, in the conservative treatment of chronic anal fissure (CAF).Methods.Among all patients with CAF observed during the study period, 31 subjects met the inclusion criteria and underwent medical therapy with Myoxinol 3% ointment every 12 hours for 6 weeks. Two patients were lost to follow-up. Clinical and manometric follow-up was carried out eight weeks after treatment.Results.At follow-up the success rate was 72.4% (21/29); median VAS score and mean anal resting pressure were significantly lower if compared with respective baseline data. The only one adverse effect of the topical application of Myoxinol 3% ointment was perianal itch, which was reported by 3,4% (1/29) of the patients available for the analysis. However, in this case this symptom did not cause interruption of the treatment.Conclusions.The topical application of Myoxinol 3% ointment in the cure of CAF shows encouraging early results. Further researches with a larger series and a longer follow-up are needed to confirm these data.

Effect of nifedipine on anorectal sensorimotor functions in health and fecal incontinence

The mechanisms of increased rectal stiffness in women with fecal incontinence (FI) and rectal urgency are not understood. Our hypothesis was that distention-induced activation of mechanosensitive L-type calcium channels in smooth muscle contributes to increased rectal stiffness in FI. Anal pressures, rectal distensibility (compliance, capacity, and contractile response to sinusoidal oscillation), and rectal sensation were assessed before and after oral nifedipine (30 + 10 mg) or placebo in 16 women with FI and 16 asymptomatic women. At baseline, FI patients had a lower anal pressure increment during squeeze (health, 66.9 ± 7.6: FI, 28.6 ± 5.9, mean ± SE, P ≤ 0.01), lower rectal capacity ( P = 0.052), and higher rectal pressures during sinusoidal oscillation (health, 13.7 ± 3.2: FI, 21.7 ± 1.4, mean ± SE, P = 0.02) than the healthy women, which suggests an exaggerated rectal contractile response to distention. Nifedipine decreased mean BP, increased heart rate ( P = 0.01 vs. placebo), and reduced anal resting pressure ( P ≤ 0.01) but did not significantly modify rectal distensibility in health or FI. Plasma nifedipine concentrations (health, 103 ± 21 ng/ml: FI, 162 ± 34 ng/ml) were correlated with increased rectal compliance ( r = 0.6, P = 0.02) in all study participants and, in healthy subjects, with decreased rectal pressures during sinusoidal oscillation ( r = 0.86, P = 0.01), indicative of reduced stiffness. No consistent effects on rectal perception were observed. These observations confirm that FI is associated with anal weakness and increased rectal stiffness. At therapeutic plasma concentrations, nifedipine reduced anal resting pressure but did not improve rectal distensibility in FI, outcomes that argue against a predominant contribution of myogenic L-type calcium channels to reduced rectal distensibility in FI.