Sildenafil citrate in the treatment of pain in primary dysmenorrhea: a randomized controlled trial.

STUDY QUESTION: Is a vaginal preparation of sildenafil citrate capable of alleviating acute menstrual pain in patients with primary dysmenorrhea (PD)? SUMMARY ANSWER: A vaginal preparation of sildenafil citrate is capable of alleviating acute menstrual pain in patients with PD with no observed adverse effects. WHAT IS KNOWN ALREADY: Oral preparations of nitric oxide (NO) donor drugs augment relaxant effects of NO on myometrial cells, reverse the vasoconstriction caused by prostaglandins and successfully alleviate pain, but the incidence of side effects is too high for routine clinical use. Sildenafil citrate inhibits type 5-specific phosphodiesterase (PDE5), thus preventing the degradation of cyclic guanosine monophosphate (cGMP) in the muscle and augmenting the vasodilatory effects of NO. Therefore, by inhibiting PDE5, the tissue remains relaxed and more blood can circulate through. It has been used previously in a vaginal form with no observed side effects, and it enhances endometrial blood flow. STUDY DESIGN, SIZE, DURATION: A double-blind, randomized, controlled trial comparing vaginal preparation of sildenafil citrate (100 mg single dose) to a placebo in 62 PD patients at the time of painful menstruation was conducted. The primary outcome was total pain relief over 4 consecutive hours (TOPAR4) comparing sildenafil citrate to placebo, where higher TOPAR4 scores represent better pain relief. Secondary outcomes were pain relief as measured by the visual analog scale (VAS) and uterine artery pulsatility index (PI). Subjects were recruited from December 2007 to January 2011. The trial was stopped due to closeout of the funding for the study. PARTICIPANTS, SETTINGS, METHODS: Participants were women in good health, were aged 18-35 years and suffered from moderate to severe PD. They were randomized to either vaginal placebo or 100 mg vaginal sildenafil citrate in a 1:1 ratio using random permuted blocks having a block size of 4. At baseline and 1, 2, 3, and 4 h post-treatment, patients were asked to provide assessment of their degree of pain using two scales: (i) pain on the 5-level ordinal scale used for TOPAR4 calculation and (ii) pain level on the VAS. The study ended 4 h after treatment initiation. MAIN RESULTS AND THE ROLE OF CHANCE: Twenty-five subjects completed the study. Using the TOPAR4 score, the sildenafil citrate group had significantly better pain relief compared with the placebo group [mean (SD): 11.9 (3.2) versus 6.4 (2.1), respectively; difference in means = 5.3; 95% CI: (2.9,7.6); P < 0.001)]. On the VAS, sildenafil citrate provided better pain relief than placebo at each time point. At the 2-h time point, the PI was significantly lower in the sildenafil citrate group compared with the placebo group [mean (SD): 1.6 (0.6) versus 2.3 (0.5), respectively; difference in means = -0.7; 95% CI: (-1.2, -0.1); P = 0.01)]. LIMITATIONS, REASONS FOR CAUTION: Since we did not meet our sample size due to the loss of funding and could not confirm our primary hypothesis, larger studies of longer duration, likely multi-center, are needed to confirm the findings from this study. WIDER IMPLICATIONS OF THE FINDINGS: A number of medications have been investigated to improve the treatment options for PD, but most have proven unsuccessful or to have an unfavorable risk/benefit ratio. Since PD is a condition that most women suffer from and seek treatment for at some point in their lives, our study offers hope that vaginal sildenafil citrate is a safe and effective option for patients who do not desire or are unresponsive to treatments now available on the market. STUDY FUNDING/COMPETING INTERESTS: Funding for this study was provided by National Institutes of Health (NIH) grants RO3 TW007438 and K24 HD01476. The authors report no relevant conflicts of interest. TRIAL REGISTRATION NUMBER: NCT00123162 (Clinical trials.gov).

Transvaginal color Doppler study of uterine blood flow in primary dysmenorrhea.

BACKGROUND: The pain in primary dysmenorrhea is caused by excessive prostaglandin production that leads to vasoconstriction and uterine ischemia. Changes in uterine blood flow are important factors in pathophysiology of primary dysmenorrhea. The aim of the study was to determine if vasoconstriction of the uterine vessels in patients with primary dysmenorrhea is detectable by transvaginal color Doppler ultrasound. METHODS: Forty-two women with primary dysmenorrhea and fifty healthy controls were included in this prospective study. Women were examined with transvaginal color Doppler ultrasound on first day of the cycle, once in the follicular and once in the luteal phase. Measurements of pulsatility index in uterine, arcuate, radial and spiral arteries were performed. Student's t-test was used to establish statistical significance between groups. RESULTS: Women in dysmenorrhea group had significantly higher uterine blood flow indices than healthy controls in all three measurements periods. This includes all vessels studied on the first day of the cycle, the radial and spiral arteries during the follicular phase and the arcuate, radial and spiral arteries during the luteal phase. CONCLUSIONS: We found that women with primary dysmenorrhea have elevated Doppler indices in uterine arteries not only on first day of the cycle but throughout the whole cycle. Therefore we postulated that primary dysmenorrhea is not only the disorder of menstruation but also a disease of a menstrual cycle as a whole.

Common form of Lyme borreliosis carditis--complete heart block with syncope: report on 3 cases.

Third degree atrioventricular (AV) heart block with severe Adams-Stokes attacks in 3 patients with Lyme borreliosis is described. All patients had similar clinical manifestations: previously healthy, they experience syncope as an abrupt onset of the disease. Data on skin changes--erythema migrans--was subsequently obtained, although the patients did not recall being bitten by a tick. Diagnoses were based on clinical manifestations and on positive serologic test results to borrelia. Following AV block returned to sinus rhythm with normal AV conduction in all patients.

[Epidemiology of Lyme borreliosis]. / Epidemiologija Lyme borreliosis.

Our prospective study covered 1093 patients with epidemiological features and demonstrable clinical manifestations of Lyme borreliosis from 1987 to 1992. Basic criteria for the inclusion of our patients in the study were: tick bite, erythema migrans and antibodies to B. burgdorferi in each patient's serum. Various clinical manifestations were found un 1034 (94.6%) patients out of whom 829 (80.2%) had a history of tick bite, 901 (87.1%) had erythema migrans and 217 (21.0%) had serologic confirmation of the diagnosis. Inapparent infection was discovered in 59 (5.4%) patients. Other Types of skin changes (II and III stage) were found in 123 (11.9%) patients. The disease resulted in neurologic, joint and cardiac manifestations in somewhat lower percentage of patients (6.3%, 6.6% and 1.5%, respectively). In the three-year period (1990-1992) microscopic examination of the ticks (Ixodes ricinus) collected at several green areas of Belgrade confirmed the presence of B. burgdorferi in 29.1 per cent.

[Investigational methods in Lyme disease]. / Metodologija istrazivanja lajmske bolesti.

After the first clinical case of Lyme disease had been recorded in Belgrade in 1987 a multi-level research of the disease was undertaken in our country. The research was organized on the team basis and was systematized. Ever since the beginning epidemiological method has been applied. Professional approach was provided by guidelines, while methods and research stages have been provided and further developed during seminars and symposiums dealing with lyme disease. Research team was comprised of experts from Institute of Public Health of Belgrade, Institute for Preventive Medicine of the Medical Military Academy and clinicians--specialists in the relevant areas. The team gathered its own precious experience in Lyme borreliosis, the disease with precisely defined features and well-described manifestations and characteristics. This work describes methodology applied in the research of Lyme disease in our country.

[Lyme disease and pregnancy]. / Lajmska bolest i trudnoca.

The authors have investigated Borrelia infection in pregnant women with two or more spontaneous abortions, but with no clinical manifestations of Lyme disease. In 42 such cases the results were negative. On the other hand, in two cases with positive epidemiologic data, but without clinical manifestations of Lyme disease, serologic findings were positive. No complications during pregnancy or after childbirth were recorded.

[Epidemiologic characteristics and serologic findings in erythema migrans]. / Epidemioloske karakteristike i seroloski nalaz kod erythema migrans.

Our three-year research covered 417 patients with erythema migrans, of both sexes and all age groups. Among them 87.3% had a history of tick bite. Average attachment of tick to a patients skin was two days. Diameter of erythematous lesions was 1-50 cm (with an average of 15.1 cm). Magnitude of the lesion does not correlate with the further development of the Lyme disease. IFA test detected antibodies against Borreliae burgdorferi in 27.0% of our patients.

[Rheumatic manifestations in Lyme borreliosis: personal experience in patients with oligoarthritis of "unknown" origin]. / Reumatske manifestacije u lajm borelioze: nasa iskustva u bolesnika sa oligoartritisom "nepoznate" prirode.

Lyme borreliosis is an infectious illness caused by the spirochete Borrelia burgdorferi and is transmitted by tick vectors. A prospective study was performed from January 1990, to investigate whether Lyme arthritis might have been undetected among patients with (unclassified arthritis) oligoarthritis of "unknown" aetiology. 210 patients were tested for antibodies to Borrelia burgdorferi: 82 patients with oligoarthritis of "unknown" aetiology; 52 patients with Reiter's syndrome; 20 patients with seronegative, B-27 positive oligoarthritis and 56 controls. Serological testing for Borrelia burgdorferi was performed by indirect immunofluorescence assay. The occurrence of positive antibodies (1:80) in 11 (13.4%) patients with arthritis of "unknown" aetiology was significantly different from the combined control group (1.6%) (p < 0.05). Four out of 11 patients remembered a tick bite, two out of 11 patients developed erythema migrans after 3 to 10 days. Six weeks later 2 patients developed oligoarthritis and one patient after a month. In the remaining 8 patients arthritis was the first sign of the disease. Knees were most commonly affected (90%). Radiographic abnormalities (osteoporosis, soft tissue swelling) were noted in 3 patients. The synovial fluid findings were typical for inflammatory arthritides in 6 patients. The diagnosis of Lyme borreliosis was made according to following data: origin from an area endemic for Lyme borreliosis, tick bite, erythema migrans, significant levels of the antibodies to the Borrelia burgdorferi and oligoarthritis. It can be concluded that arthritis may be the main manifestation of Borrelia burgdorferi infection.

[The clinical picture of Lyme disease in neurology]. / Klinicki oblici lajmske bolesti u neurologiji.

Neuroborreliosis of central and peripheral nervous system was found in 24 patients with typical and atypical clinical syndromes. Information about tick bite was obtained in only 1/3 of our patients. Specific antibodies were found in 3/4 by flourescent antibody test, oligoclonal bands in 1/2, and signs of inflammation in cerebrospinal fluid in 1/3 of patients. The majority had favourable reaction to antibiotic therapy. It is necessary to investigate every case of suspected neuroborreliosis because it can imitate many neurological diseases. One must insist on information about the tick bite and/or erythema migrans and search for specific antibody production, both in blood and cerebrospinal fluid.

[Clinical picture of cardioborreliosis: from AV block to perimyocarditis]. / Klinicki oblici kardioborelioze: od A-V bloka do perimiokarditisa.

The third degree A-V heart block with severe Adams-Stokes attacks in nine patients with Lyme borreliosis was described. All patients had similar clinical picture: previously healthy with syncope as abrupt onset of the disease. Data on skin changes--erythema migrans--were obtained subsequently although the patients did not recall being bitten by a tick. Diagnosis was based on clinical manifestation, and on positive serologic tests to Borrelia. After the administered therapy (on admission atropine 0.5 mg i.v., and/or isoproterenol 0.02 mcg/kg/min, temporary pace-maker in two patients; and after proved diagnosis penicillin 20 mil. unit per day 10 days, and tetracyclin 2.0 gr per day 20 days A-V block returned to sinus rhythm with normal A-V conduction, and all biochemical parameters returned to normal limits. Perimyocarditis is not rare during Lyme borreliosis, but in this case infection syndrome is dominant.

[Chronic encephalomyelitis caused by Borrelia burgdorferi. Case report]. / Hronicni encefalomijelitis izazvan Borelijom burgdorferi. Prikaz slucaja.

We present a female patient with typical third stage neuroborreliosis with progressive chronic encephalomyelitis. One month after a tick bite, in the first stage of Lyme disease, she had myalgias during ten days and after one year polyarthralgias and polyarthritis. Neurological problems occurred 15 years after the tick bite with headache, nystagmus, intentional tremor and spastic paraparesis with sphincter disturbances. Etiological diagnosis was established after three years. Cytobiochemical findings in cerebrospinal liquor were normal but oligoclonal IgG bands were found. Fluorescent antibody test was positive in serum (1:75) as well as ELISA (1:447). The patient reacted favourably to intravenous crystal penicillin 20 x 10(6) units daily during 18 days. Till now, she is in remission and has only mild paresis of the left leg.

[Lyme borreliosis in Belgrade]. / Lyme borreliosis u Beogradu.

In the period 1990-1992 in Belgrade area a diagnosis of Lyme disease was registered in 487 patients. There were 195 men and 292 women. The disease was registered in all ages groups, median age 38 y. The tick bite has been confirmed in 379 (77.8%) patients. Erythema migrans was the first sign of illness in 387 (84.6%) patients. The disease resoted in neurologic symptoms in 1.8%, joint manifestation in 4.8% and cardiac involvement in 0.9%. Antibodies to Borrelia burgdorferi have been detected by indirect immunofluorescence microscopy in 23.4%. Lyme disease has been registered in all districts of Belgrade. Acarological investigations have detected an infection by Borrelia burgdorferi in 29.0% of investigated ticks.

[Rhombencephalitis as a manifestation of neuroborreliosis]. / Rombencefalitis kao manifestacija neuroborelioze.

Rhombencephalitis is a rare neurological manifestation of stage II of Lyme disease. We presented two cases with no recollection of tick bite nor erythema migrans and with cranial nerve nuclei, pyramidal tract and cerebellar tracts involvement of sudden onset, inflammatory syndrome in cerebrospinal liquor, positive oligoclonal bands and elevated IgG index. A spontaneous remission occurred in both cases, but antibiotic was given intravenously for prevention of relapses and disease progression.

[Modern immunologic tests in the diagnosis of Lyme borreliosis]. / Savremeni imunoloski testovi u dijagnostici lajm borelioze.

In this work we described the results that were obtained using various immunodiagnostic assays for the detection of lyme borreliosis. Sera of the patients that were in acute or chronical phase of the disease were analysed in indirect immunofluorescent, immunoenzyme and immunoblot assays which were prepared and carried out in our laboratory. As a control for the validity of these investigations, we used sera of the healthy people, as well as of the patients suffering of lues or rheumatoid illnesses. Results that we obtained pointed out the factors responsible for the nonspecific reactions in indirect immunofluorescent and immunoenzyme test. The advantage of the immunoblot analysis in detecting lyme borreliosis is described in this work.

[Ecology of Borrelia burgdorferi]. / Ekologija Borelije burgdorferi.

Much still remains to be understood about ecology of Borrelia burgdorferi which is transmitted by a number of ticks belonging primarily to the Ixodes complex, known to feed on different animal hosts and humans. This article pretends to be a review of previous knowledge of Borrelia burgdorferi ecology. Special emphasis is placed on the preliminary results of an investigation conducted in Yugoslavia on the risk of developing lyme borreliosis after a tick bite (Ixodes ricinus). Lyme borreliosis was studied prospectively in 147 persons with tick fastened on them. Dark-field microscopic examination of tick mitgut revealed that 11 (7.9%) od 147 Ixodes ricinus were infected with Borrelia burgdorferi. Lyme borreliosis was demonstrated in only one (0.6%) of all persons bitten by ticks infected with Borrelia burgdorferi. In conclusion, these preliminary data indicate that in Yugoslavia lyme borreliosis infrequently occurred after a tick bite.

[Vectors of Borrelia burgdorferi]. / Vektori Borrelia burgdorferi.

During the period 1990-1992-5,915 ticks were collected and identified in the area of Belgrade. Identification has shown that 99.8% were Ixodes ricinus and 0.2% Dermacentor marginatus. Infection with Borrelia burgdorferi was found in 27.0% to 31.7%. Females were more often infected than males and nymphs more often than larvae. Tick infection was at lowest degree in parks, little bit higher in woods and highest in mixed park-wood areas. Out of 28 locations, six can not be defined as foci of Lyme borreliosis, two are defined as potential foci and 20 as active foci of Lyme borreliosis. In a three year period we have isolated Borrelia burgdorferi in five occasions; in one occasion from ticks collected in Barajevo and in four occasions from ticks collected in Kosutnjak.

[A theoretical model for the study of Lyme borreliosis]. / Teorijski model izucavanja lajm borelioze.

This article is a short review of: a) development of theory on natural foci of communicable diseases in man, b) methodological approach to the investigation of natural foci, e.g. theoretical model in their investigation, and c) the use of theoretical model in the investigation of Lyme borreliosis. A great number of multidisciplinary studies on natural foci zooanthroponoses conducted through many years, in which ecological approach and numerous methods were applied, commencing from studies of the processes at the level of molecules, genes, cells, tissues, organismus, populations and species, contributed to the knowledge that epizootical process of natural foci of zooanthroponoses is almost an ideal natural model. Its investigation allows the establishment of the rules of epidemiological process which, for many reasons (ethical above all), is not accessible for experimental studies. On these principles a general block model has been worked out, which serves for the estimation of epidemiological manifestations of natural foci zooanthroponoses, and which, applied to Lyme borreliosis, enables the determination of active and potential foci and the estimation of the degree of risk of man infection in determined foci. Data obtained in such a way allow planning and application of adequate preventive measures.

[The first isolation of Borrelia burgdorferi in Apodemus flavicollis in Yugoslavia]. / Prva izolacija Borrelia burgdorferi is Apodemus flaviccolis-a u Yugoslaviji.

Small rodent species, as well as their ectoparasitic fauna, and the presence of Borrelia burgdorferi in their blood and internal organs (liver and spleen) was investigated, at two locations (Kosutnjak, Lipovicka suma) in Belgrade. Animals were caught between September 15-17, 1992. On location Kosutnjak two Apodemus flavicollis were trapped and Borrelia burgdorferi was isolated from the spleen of one of them. On location Lipovicka suma 13 rodents were trapped as follows: 10 Apodemus flavicollis, 2 Apodemus agrarius and one Mus musculus. In these the presence of Borrelia burgdorferi was not determined. Ectoparasits Ixodes ricinus, Nesopyllus fasciatus and Haemogamasus spp. have been found. The location Kosutnjak can be considered as an active focus of lyme borreliosis.

[Ixodes ricinus proven as a vector of Lyme borreliosis in Yugoslavia]. / Ixodes ricinus dokazan vektor lajm borelioze i u Jugoslaviji.

263 fasting female Ixodes ricinus were examined for Borrelia burgorferi, the vector of Lyme borreliosis. Female ticks were collected by flagella in the biotopes (Belgrade and Osijek) in which ticks bite patients with Lyme borreliosis. Borrelia burgorferi was proved in 58 (22%) of 263 female ticks in the native preparations of the intestinal contents by darkfield microscopy. In macerates of two groups of 5 female ticks each, Borrelia burgorferi was isolated by cultivation in the modified Kelly nutrient media for borrelia. The supposition that Ixodes ricinus is the vector of Lyme borreliosis in Yugoslavia is confirmed.