Metastatic renal cell carcinoma to the brain: optimizing patient selection for gamma knife radiosurgery.

INTRODUCTION: The effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied. METHODS AND MATERIALS: Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n = 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE). RESULTS: One hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS. CONCLUSIONS: We identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.

Adaptive radiosurgery based on two simultaneous dose prescriptions in the management of large renal cell carcinoma brain metastases in critical areas: Towards customization.

BACKGROUND: The long-term benefits of local therapy in metastatic renal cell carcinoma (mRCC) have been widely documented. In this context, single fraction gamma knife radiosurgery (SF-GKRS) is routinely used in the management of brain metastases. However, SF-GKRS is not always feasible due to volumetric and regional constraints. We intend to illustrate how a dose-volume adaptive hypofractionated GKRS technique based on two concurrent dose prescriptions termed rapid rescue radiosurgery (RRR) can be utilized in this particular scenario. CASE DESCRIPTION: A 56-year-old man presented with left-sided hemiparesis; the imaging showed a 13.1 cc brain metastasis in the right central sulcus (Met 1). Further investigation confirmed the histology to be a metastatic clear cell RCC. Met 1 was treated with upfront RRR. Follow-up magnetic resonance imaging (MRI) at 10 months showed further volume regression of Met 1; however, concurrently, a new 17.3 cc lesion was reported in the boundaries of the left frontotemporal region (Met 2) as well as a small metastasis (<1 cc) in the left temporal lobe (Met 3). Met 2 and Met 3 underwent RRR and SF-GKRS, respectively. RESULTS: Gradual and sustained tumor ablation of Met 1 and Met 2 was demonstrated on a 20 months long follow- up. The patient succumbed to extracranial disease 21 months after the treatment of Met 1 without evidence of neurological impairment post-RRR. CONCLUSION: Despite poor prognosis and precluding clinical factors (failing systemic treatment, eloquent location, and radioresistant histology), RRR provided optimal tumor ablation and salvage of neurofunction with limited toxicity throughout follow-up.

Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005-2014.

BACKGROUND AND PURPOSE: Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA). MATERIAL AND METHODS: mRCC patients (n = 117) treated with SRT (n = 57), SM (n = 30) or both modalities sequentially (n = 30) at two oncological centres in Sweden in 2005-2014 were retrospectively included. Median follow-up (mFU) was 63 months. RESULTS: A majority had clear cell histology, 1-3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6-5.2; p < 0.001), intracranial targets (HR 1.8; CI 1.1-3.2; p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2-0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients (n = 60) were relapse-free with mFU of 87 months. CONCLUSIONS: OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis.

Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression.

Depression is usually associated with alterations in the monoaminergic system. However, new evidences suggest the involvement of the glutamatergic system in the aetiology of depression. Here we explored the glutamatergic system in a rat model of depression (i.e., the flinders sensitive line (FSL)) to reveal the mechanism underlying the emotional and cognitive aspects associated with the disease. We showed a dramatically elevated level of baseline glutamatergic synaptic transmission by whole-cell recordings as well as impairment in long-term potentiation induced by high-frequency stimulation in hippocampal slices from FSL rats compared with Sprague-Dawley rats. At behavioural level, FSL rats displayed recognition memory impairment in the novel object recognition test. Enantioselective chromatography analysis revealed lower levels of D-serine in the hippocampus of FSL rats and both synaptic plasticity and memory impairments were restored by administration of D-serine. We also observed dysfunctional astrocytic glutamate regulation including downregulation of the glia glutamate transporter GLAST as shown by western blot. One possibility is that the dysfunctional astrocytic glutamate reuptake triggers a succession of events, including the reduction of D-serine production as a safety mechanism to avoid NMDA receptor overactivation, which in turn causes the synaptic plasticity and memory impairments observed. These findings open up new brain targets for the development of more potent and efficient antidepressant drugs.

Omega-3 from fish oil augments GVHD through the enhancement of chemotherapy conditioning regimen and selective FoxP3 depletion.

Omega-3 is known to enhance the effects of several chemotherapeutic agents and to exert several immunoregulatory actions In the present study, we evaluated the effects of a 21-day feeding regimen with omega-3-rich fish oil (FO) and its corresponding control, omega-6 rich corn oil (CO), on the BU-CY conditioning and the development of GVHD after BMT in mice. Before conditioning, FO, but not CO, feeding caused a significant attenuation in the number and functionality of splenic FoxP3+ T regulatory cells (Treg). FO feeding also enhanced the effects of the conditioning through severe depletion of Treg cells in the spleen and CD11b+ myeloid cells in both the BM and spleen. Consequently, FO-fed animals conditioned with BU-CY showed exacerbated GVHD following transplantation with allogeneic BM and splenic cells. In contrast, identical transplantation in CO-fed mice resulted in poor engraftment and body weight loss. Moreover, in standard-fed recipients, BMT with cells from FO-fed donors resulted in moderate GVHD and improved the survival time, whereas BMT with cells from CO-fed donors shortened the survival time and caused anemia. We conclude that food supplements should be considered in patients undergoing BMT and/or chemotherapy treatment.

Modelling of DARPP-32 regulation to understand intracellular signaling in psychiatric disease.

The majority of psychopharmaca acts by binding to G-protein coupled receptors and thereby asserts it's action through the regulation of intracellular signaling networks. The convergence and interactions of pathways within these networks make the detailed signaling hard to study experimentally, and the response to a stimuli can be non-intuitive. To approach these problems with systems biology and merging biochemical data in a computer model to do virtual experiments with high time-resolution can shed new light on the functioning of these networks. The phosphoprotein DARPP-32 is regulated by several modulatory neurotransmitters, including dopamine, serotonin and adenosin, and it's function has been proposed to be altered in schizophrenia. Moreover, the well studied regulation of DARPP-32, and the vast amount of biochemical data makes it a model molecule when it comes to intracellular signaling. To better understand the interactions of the pathways that regulate DARPP-32 activation we constructed a computer model based on experimental data. In this work we discovered unexpected responses of DARPP-32 at fast timescales. An equally important outcome of the work was to identify areas where additional work is needed in order to understand intracellular signaling at the systems level, showing the need for close collaborations between theoretical and experimental biologists.

Noninvasive estimation of tumour viability in a xenograft model of human neuroblastoma with proton magnetic resonance spectroscopy (1H MRS).

The aim of the study was to evaluate proton magnetic resonance spectroscopy ((1)H MRS) for noninvasive biological characterisation of neuroblastoma xenografts in vivo. For designing the experiments, human neuroblastoma xenografts growing subcutaneously in nude rats were analysed in vivo with (1)H MRS and magnetic resonance imaging at 4.7 T. The effects of spontaneous tumour growth and antiangiogenesis treatment, respectively, on spectral characteristics were evaluated. The spectroscopic findings were compared to tumour morphology, proliferation and viable tumour tissue fraction. The results showed that signals from choline (Cho)-containing compounds and mobile lipids (MLs) dominated the spectra. The individual ML/Cho ratios for both treated and untreated tumours were positively correlated with tumour volume (P<0.05). There was an inverse correlation between the ML/Cho ratio and the viable tumour fraction (r=-0.86, P<0.001). Higher ML/Cho ratios concomitant with pronounced histological changes were seen in spectra from tumours treated with the antiangiogenic drug TNP-470, compared to untreated control tumours (P<0.05). In conclusion, the ML/Cho ratio obtained in vivo by (1)H MRS enabled accurate assessment of the viable tumour fraction in a human neuroblastoma xenograft model. (1)H MRS also revealed early metabolic effects of antiangiogenesis treatment. (1)H MRS could prove useful as a tool to monitor experimental therapy in preclinical models of neuroblastoma, and possibly also in children.

Dopamine D(1) receptor-induced gene transcription is modulated by DARPP-32.

The role of the dopamine- and cyclic AMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) in dopaminergic regulation of gene transcription in striatum and globus pallidus was examined. Mice with targeted disruption of the gene encoding DARPP-32, its homologue, inhibitor-1, or both, were used. Pharmacological characterization showed that mutant mice had normal basal levels of dopamine D(1) and D(2) receptors and adenosine A(2A) receptors. Basal expression levels of the striatonigral-specific neuropeptides substance P and prodynorphin and the immediate early genes c-fos and NGFI-A were also unaltered in mutant mice. A full D(1) receptor agonist, SKF 82958, up-regulated the expression of these neuropeptides and immediate early genes significantly more in wild-type mice than in mice lacking DARPP-32. Moreover, the additive stimulation of SKF 82958 and quinelorane, a D(2) receptor agonist, on c-fos mRNA in globus pallidus was significantly decreased in DARPP-32 and DARPP-32/I-1 knockout mice. No changes in dopamine receptor-induced gene expression were found in I-1 knockout mice. These results demonstrate an important involvement of DARPP-32 in dopamine receptor-mediated regulation of gene expression both in striatal neurons, which are enriched in DARPP-32, and in pallidal neurons, which do not contain DARPP-32.

Regulation of tyrosine hydroxylase activity and phosphorylation at Ser(19) and Ser(40) via activation of glutamate NMDA receptors in rat striatum.

The activity of tyrosine hydroxylase, the rate-limiting enzyme in the biosynthesis of dopamine, is stimulated by phosphorylation. In this study, we examined the effects of activation of NMDA receptors on the state of phosphorylation and activity of tyrosine hydroxylase in rat striatal slices. NMDA produced a time-and concentration-dependent increase in the levels of phospho-Ser(19)-tyrosine hydroxylase in nigrostriatal nerve terminals. This increase was not associated with any changes in the basal activity of tyrosine hydroxylase, measured as DOPA accumulation. Forskolin, an activator of adenylyl cyclase, stimulated tyrosine hydroxylase phosphorylation at Ser(40) and caused a significant increase in DOPA accumulation. NMDA reduced forskolin-mediated increases in both Ser(40) phosphorylation and DOPA accumulation. In addition, NMDA reduced the increase in phospho-Ser(40)-tyrosine hydroxylase produced by okadaic acid, an inhibitor of protein phosphatase 1 and 2A, but not by a cyclic AMP analogue, 8-bromo-cyclic AMP. These results indicate that, in the striatum, glutamate decreases tyrosine hydroxylase phosphorylation at Ser(40) via activation of NMDA receptors by reducing cyclic AMP production. They also provide a mechanism for the demonstrated ability of NMDA to decrease tyrosine hydroxylase activity and dopamine synthesis.

Regulation of the phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors.

Dopamine D(1), dopamine D(2), and adenosine A(2A) receptors are highly expressed in striatal medium-sized spiny neurons. We have examined, in vivo, the influence of these receptors on the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). DARPP-32 is a potent endogenous inhibitor of protein phosphatase-1, which plays an obligatory role in dopaminergic transmission. A dose-dependent increase in the state of phosphorylation of DARPP-32 occurred in mouse striatum after systemic administration of the D(2) receptor antagonist eticlopride (0.1-2.0 mg/kg). This effect was abolished in mice in which the gene coding for the adenosine A(2A) receptor was disrupted by homologous recombination. A reduction was also observed in mice that had been pretreated with the selective A(2A) receptor antagonist SCH 58261 (10 mg/kg). The eticlopride-induced increase in DARPP-32 phosphorylation was also decreased by pretreatment with the D(1) receptor antagonist SCH 23390 (0.125 and 0.25 mg/kg) and completely reversed by combined pretreatment with SCH 23390 (0.25 mg/kg) plus SCH 58261 (10 mg/kg). SCH 23390, but not SCH 58261, abolished the increase in DARPP-32 caused by cocaine (15 mg/kg). The results indicate that, in vivo, the state of phosphorylation of DARPP-32 and, by implication, the activity of protein phosphatase-1 are regulated by tonic activation of D(1), D(2), and A(2A) receptors. The results also underscore the fact that the adenosine system plays a role in the generation of responses to dopamine D(2) antagonists in vivo.

Activation of dopamine D2 receptors decreases DARPP-32 phosphorylation in striatonigral and striatopallidal projection neurons via different mechanisms.

The vast majority of striatal neurons are GABAergic medium-sized spiny neurons. These cells receive glutamatergic input from the cortex, thalamus and limbic areas and dopaminergic input from the mesencephalon. Most relevant evidence indicates that dopamine D1 receptors are located on striatonigral projection neurons, and that adenosine A2A receptors and most dopamine D2 receptors are located on striatopallidal projection neurons (see, however, Refs I and 13). Here we have utilized regulation of the phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein of mol. wt 32,000 (DARPP-32) to study the possible interactions among nigrostriatal dopaminergic neurons and the two classes of dopaminoceptive target neurons. We show that, in striatal slices, the D2 receptor agonist, quinpirole, strongly inhibits the phosphorylation of DARPP-32 induced by either the D1 receptor agonist, SKF 81297, or the A2A receptor agonist, CGS 21680. Tetrodotoxin abolished the effect of quinpirole on the D1 agonist-induced but not the A2A agonist-induced phosphorylation of DARPP-32. These data indicate that: (i) adenosine A2A and dopamine D2 receptors interact within the same striatopallidal neurons, and (ii) D2 receptors present on the striatopallidal neurons modulate the effects of D1 receptors on the striatonigral neurons. Thus, a single neurotransmitter is capable of activating distinct classes of receptors on distinct populations of target neurons, which, in turn, interact with each other through intercellular communication.

Mu- and delta-opioid receptor agonists inhibit DARPP-32 phosphorylation in distinct populations of striatal projection neurons.

In the striatum, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) is highly expressed by virtually all projection medium-sized spiny neurons. cAMP-dependent phosphorylation of DARPP-32 is stimulated via activation of dopamine D1 receptors in striatonigral neurons, and via activation of adenosine A2A receptors in striatopallidal neurons. In this study, we have examined the contribution of mu-, delta- and kappa-opioid receptors to the regulation of DARPP-32 phosphorylation, in rat striatal slices. The results show that, at low concentrations (100 pm-1 nm), the mu-opioid agonist, Tyr-D-Ala-Gly-N-Me-Phe-glycinol (DAMGO), inhibits the increase in DARPP-32 phosphorylation induced by activation of D1, but not by activation of A2A receptors. Conversely, the delta-receptor agonist, Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE), inhibits DARPP-32 phosphorylation induced by activation of A2A, but not by activation of D1 receptors. The kappa-receptor agonist, U50488, does not affect DARPP-32 phosphorylation induced by either D1 or A2A agonists. Thus, mu-opioid receptors interact with dopamine D1 receptors on striatonigral neurons, whereas delta-opioid receptors interact with adenosine A2A receptors on striatopallidal neurons. These results suggest that regulation of DARPP-32 phosphorylation is involved in mediating some of the effects exerted by enkephalin on striatal medium-sized spiny neurons.

Activation of adenosine A2A and dopamine D1 receptors stimulates cyclic AMP-dependent phosphorylation of DARPP-32 in distinct populations of striatal projection neurons.

In the striatum, adenosine A2A and dopamine D1 receptors are segregated in striatopallidal and striatonigral projection neurons, respectively. In this study, we have examined the effects of activating adenosine A2A and dopamine D1 receptors on the state of phosphorylation of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of mol. wt 32,000), a potent endogenous regulator of protein phosphatase-1 that is highly expressed in striatal medium-sized spiny neurons. In rat striatal slices, the D1 receptor agonist SKF 81297 and the A2A receptor agonist CGS 21680 transiently increased the levels of phosphorylated DARPP-32 in a concentration-dependent manner. In the same preparation, the two agonists were also able to induce a significant increase in cyclic AMP formation. When striatal slices were incubated with a combination of CGS 21680 and SKF 81297, the effects of the two agonists on both DARPP-32 phosphorylation and cyclic AMP formation were additive. The maximal effects of SKF 81297 and CGS 21680 on DARPP-32 phosphorylation were of similar magnitude, and were completely abolished by the cyclic AMP-dependent protein kinase inhibitor, Rp-cAMPS. The present results show that DARPP-32 phosphorylation in the striatum is stimulated by adenosine, acting on A2A receptors, and dopamine, acting on D1 receptors, and that cyclic AMP is the mediator in both cases. Our data also suggest that dopamine and adenosine regulate the state of phosphorylation of DARPP-32 in distinct sub-populations of medium-sized spiny neurons expressing dopamine D1 and adenosine A2A receptors, respectively.

Oestradiol-releasing vaginal ring for treatment of postmenopausal urogenital atrophy.

A silicone vaginal ring releasing 5-10 micrograms oestradiol/24 h for a minimum of 90 days has been developed for treatment of urogenital mucosal atrophy. The efficacy, safety and acceptability of the oestradiol-releasing ring were studied in 222 postmenopausal women with symptoms and signs of atrophic vaginal mucosa. The maturation of the vaginal epithelium, as measured by cytological parameters, was significantly improved during treatment. No proliferation of the endometrium was encountered. The therapy had a significant effect on symptoms (vaginal dryness, pruritus vulvae, dyspareunia, urinary urgency) and on signs of atrophic vaginitis, with cure/improvement registered in > or = 90%. The patient acceptability was high, since > or = 90% did not report any discomfort with the ring. Almost all of the sexually active women had the ring in place during coitus and in < or = 2% of cases discomfort was noticed by them or the partner. It is concluded that a vaginal silicone ring giving a continuous release of an ultra-low dose of oestradiol is an effective and safe treatment for urogenital oestrogen deficiency. No addition of progestagen is needed.

Effect of combined treatment with phenylpropanolamine and estriol, compared with estriol treatment alone, in postmenopausal women with stress urinary incontinence.

Twenty-nine postmenopausal women with slight to severe stress urinary incontinence and estrogen deficiency symptoms in the urogenital tract were treated with estriol, p.o. 4 mg once daily, and either phenylpropanolamine (PPA), p.o. 50 mg twice daily, or placebo for periods of 6 weeks according to a randomized double-blind crossover schedule. At urodynamic recordings the maximum urethral closure pressure increased by 22% with combined treatment (p less than 0.001) and an additional effect of PPA to estriol was shown (p = 0.022). The pressure transmission ratio increased, by about 15%, with both treatments (p less than 0.07). The number of leakage episodes was reduced by 28% with combined treatment (p = 0.007), but not with estriol alone (p = 0.08). Both combined treatment and estriol alone reduced significantly (p less than 0.01) the urinary incontinence complaints. Twelve women (43%) preferred combined treatment, while 7 (25%) preferred estriol alone. In women with initially slight to very severe urine loss, combined treatment reduced also (p = 0.02) the amount of urine loss, measured at a standardized physical stress test. Signs of estrogen deficiency in vulva, vagina and urethra were reduced, 75% (p less than 0.001) or 65% (p = 0.001) with estriol given in combination with PPA or alone. Maturation index of both urethral and vaginal epithelium displayed significant changes. It is concluded that the combined treatment, PPA + estriol, by affecting both the muscular and mucosal factor of the urethra, is more effective than estriol alone for treatment of female stress urinary incontinence in the postmenopausal ages.

Vaginal rings for continuous low-dose release of oestradiol in the treatment of urogenital atrophy.

Silicone vaginal rings for the continuous release of 17 beta-oestradiol (E2) with 2 constant in vitro release rates were used for the treatment of symptoms of urogenital atrophy in 2 groups of postmenopausal women. The very low dose of 7 micrograms/24 h was found to alleviate atrophic symptoms effectively and to induce significant maturation of vaginal and urethral epithelium. After a brief initial peak, the serum levels of E2 over 3 mth of treatment remained close to the detection limit. The 'undetectable' E2 release pattern was reflected only in increased levels of oestrone sulphate. There was no evidence of a systemic metabolic response and patient acceptance of the method was excellent. Continuous low-dose release of E2 via vaginal rings consequently offers an alternative means of administering local oestrogen therapy which may be particularly suitable for geriatric patients.

Estrogens and phenylpropanolamine in combination for stress urinary incontinence in postmenopausal women.

Thirty-six postmenopausal women with objectively verified stress incontinence were treated with oral estriol (Triovex, 2 mg x 1) and phenylpropanolamine (Kontexin, 50 mg x 2) alone and in combination. After an initial four-week single-blind period with phenylpropanolamine (PPA), either estriol or estriol and PPA were given randomly in four-week periods, in a crossover design. PPA and estriol in combination as well as PPA alone, raised the intraurethral pressure and significantly reduced the urinary loss by 35 per cent in a standardized physical strain test. In women with an initial low urethral pressure estriol also induced pressure increase. The leakage episodes and the assessed leakage amounts were significantly reduced by both estriol and PPA given separately as single treatment (28%) or when given as combined therapy (40%). Most of the women preferred the combined treatment to either drug alone. Additive but no synergistic effects are indicated.

Phenylpropanolamine in treatment of female stress urinary incontinence. Double-blind placebo controlled study in 24 patients.

Twenty-four women with stress urinary incontinence of slight to moderate grade were treated with phenylpropanolamine (PPA), po 50 mg twice daily, and placebo for periods of two weeks according to randomized double-blind cross-over schedule. A significant increase in maximum urethral closure pressure (MUCP) was found after treatment with PPA compared to placebo, but functional urethral length was unchanged. Number of leakage episodes were significantly reduced during PPA treatment, but micturition frequency was unchanged. Fourteen women preferred PPA, 4 preferred placebo, and 6 considered PPA and placebo to be ineffective. The scored improvements obtained by PPA were highly significant when tested against the scored placebo effect. There was a significant correlation between subjective assessment and improvement in number of leakage episodes and increase of MUCP. Plasma-PPA levels showed no significant correlation with any of the effect variables. Adverse reactions were few and negligible.

The effect of phenylpropanolamine on female stress urinary incontinence.

In a randomized double-blind manner, 43 women with grade I and II stress urinary incontinence were treated with either phenylpropanolamine p.o. 50 mg twice daily (Rinexin, 1 tablet b.i.d.) or placebo during two weeks. Urethral CO2 profilometry, with recording of maximum urethral closure pressure (MUCP) and functional urethral length (FUL), and subjective response were considered for effect evaluation. The subjective response of Rinexin was highly significant (p = 0.01) above that of placebo. Clinical improvement was reported by 15 of 21 women on Rinexin and by 8 of 22 women on placebo. A significant increase in MUCP, 14%, was registered in women on Rinexin treatment. This increase was more pronounced in the grade I than in the grade II incontinent women. No statistically significant correlations were obtained between subjective response and increase in MUCP. An increase in FUL was recorded in both two treatment groups, but no statistically significant difference between them was obtained. Adverse drug reactions were rare. No changes in blood pressure occurred. Based on the present study, Rinexin (1 tablet b.i.d.) is an effective and safe medication for female grade I and II stress incontinence and is also recommended as adjunctive therapy to physiotherapy before Teflon injection or operation.