Clinical evaluation of salivary indices and levels of Streptococcus mutans and Lactobacillus in patients treated with Occlus-o-Guide.

AIM: The aim of this study was to assess the changes over time associated with salivary indices and the presence of Streptococcus mutans and Lactobacillus in patients treated with Occlus-o-Guide. MATERIALS AND METHODS: Two groups of patients were evaluated: a test group of 20 patients treated with Occlus-o-Guide and a control group of 20 patients not subjected to orthodontic treatment. Both groups were homogeneous for age and sex. We examined the levels of S. Mutans and Lactobacillus, the salivary flow, the buffer capacity of saliva and the Sillness and Loe plaque index (PI). The samples were taken at baseline (T0), after 3 months (T1) and after 6 months of treatment (T2). All data were compared using Student's t test. RESULTS: The percentage of patients with a level of Streptococcus mutans able to cause caries was decreased in the test group (T0 = 10%, T1 = %, T2 = 0%) compared to the control group (T0 = 0%, T1 = 5%, T2 = 35%), whereas the amount of Lactobacilli was different (test group T0 = 15%, T1 = 0%, T2 = 10%; control group T0 = 0%, T1 = 5%, T2 = 35%). The total salivary flow was increased in the test group (T0 = 47, T1 = 61, T2 = 61) compared to the control group, in which it had remained almost constant (T0 = 44, T1 = 45, T2 = 45). The buffer capacity of saliva was unchanged in both groups over time; the sum of PI-plaque indices was reduced in the test group (T0 = 3, T1 = 0, T2 = 2) compared to the control group (T0 = 0, T1 = 14, T2 = 27). CONCLUSION: Despite the presence of the Occlus-o-Guide device, patients are able to maintain a good level of oral hygiene, showing improvements of the examinated parameters at follow-ups.

SPARTACUS: underdiagnosis of chronic daily headache in primary care.

Despite the burden of chronic daily headache (CDH), general practitioners' (GPs) ability to recognize it is unknown. This work is a sub-study of a population-based study investigating GPs' knowledge on their CDH patients. Patients diagnosed with CDH through the screening questionnaire were interviewed by their GPs who indicated if subjects were known as patients suffering from CDH with medication overuse (MO), CDH without MO, episodic headache (EH) or non-headache sufferers. Our study showed that 64.37 % of CDH sufferers are misdiagnosed by their GPs. However, overusers are better known to GPs.

Local estrogens for quality of life and sexuality in postmenopausal women with cardiovascular disease.

Urogenital aging and female sexual dysfunction (FSD) are significant problems following menopause. Estrogen decline is one of the key factors contributing to sexual functioning because of its crucial role for genital arousal (vasocongestion and lubrication) and other domains of the sexual response. Several common medical conditions, including cardiovascular disease (CVD), may interfere with women's sexual response across the aging process. FSD is one of the most common CVD-related quality-of-life complications with a major impact on patients' and their sexual partners' life. There is no evidence that FSD may represent an early indication of cardiovascular risk in postmenopausal women. In spite of the high prevalence, FSD remains largely under-recognized and sexual counseling is an important consideration for the proper management of postmenopausal women with CVD. Many local estrogen products are available (creams, tablets, suppositories, pessaries and rings) and are equally effective for treatment of vaginal atrophy. When a history of CVD is present, local estrogens may be safely used to treat urogenital atrophy with a significant improvement of sexual health and quality of life.

LEI (Lack of tEstosterone Impact) survey in a clinical sample with surgical menopause.

OBJECTIVES: To assess perception of sexuality and awareness of the impact of testosterone on sexual desire in a clinical sample of Italian women with surgical menopause. METHODS: In the present cross-sectional study, a structured interview on sexuality-related menopausal symptoms, attitudes towards sexuality and menopausal profile was administered to 568 women (age range 35-69 years) with bilateral oophorectomy with and without hysterectomy for benign conditions. RESULTS: The majority of women (58% yes; 36% most of the time) reported they were satisfied with their sexual life before surgical menopause. After oophorectomy, 79.3% noted the appearance/worsening of vaginal dryness, whereas the reduction of sexual desire was reported by 78.7%. Women with low sexual desire (n = 436) were significantly distressed (59.7%) and reported an impairment (24.8% yes/yes, very much) in the relationship with their partner. Sexual reactions of the partner reported by women included reduced sexual desire (17.8%), sexual dysfunction (5.1%) and fears of giving pain/lack of pleasure (28.3%). A high number of women (88.2%) would be willing to discuss sexual matters with their doctors and would consider therapeutic options. Only 36.8% were aware that a lack of testosterone might impact on sexual desire but 71% would like to know more about the role of testosterone. Hormone replacement therapy was used by 38.4% of the women. CONCLUSIONS: These data suggest that women experience significant vaginal dryness and low sexual desire and report a significant distress in the relationship with their partner after surgical menopause. Sexual counseling is mandatory in order to discuss potential therapeutic strategies, including testosterone use.

Oral breathing and dental malocclusions.

AIM: Aim of the present study was to evaluate existing correlations between oral breathing and dental malocclusions. METHODS: The study was conducted on a paediatric group of 71 oral breathers selected at the Allergology and Paediatric Immunology Department of Umberto I General Hospital, University of Rome "La Sapienza" (Italy). The children were selected based on inclusion/exclusion criteria. Children aged 6 to 12 years with no history of craniofacial malformations or orthodontic treatment were included. The results were compared with a control group composed of 71 patient aged 6 to 12 years with nasal breathing. After their medical history was recorded, all patients underwent orthodontic/otolaryngological clinical examinations. The following diagnostic procedures were then performed: latero-lateral projection teleradiography, orthopantomogram, dental impressions, anterior rhinomanometry before and after administering a local vasoconstrictor, nocturnal home pulse oximetry (NHPO) recording, spirometry test, skin prick test, study cast evaluation and cephalometric analysis following Tweed's principles. The intraoral examination assessed: dental class type, overbite, overjet, midlines, crossbite, and presence of parafunctional oral habits such as atypical swallowing, labial incompetence, finger sucking and sucking of the inner lip. Evaluation of the study casts involved arch perimeter and transpalatal width assessment, and space analysis. RESULTS: The results showed a strong correlation between oral breathing and malocclusions, which manifests itself with both dentoskeletal and functional alterations, leading to a dysfunctional malocclusive pattern. CONCLUSION: According to the authors' results, dysfunctional malocclusive pattern makes it clear that the association between oral breathing and dental malocclusions represents a self-perpetuating vicious circle in which it is difficult to establish if the primary alteration is respiratory or maxillofacial. Regardless, the problem needs to be addressed and solved through the close interaction of the paediatrician, otorhinolaryngologist, allergologist and orthodontist.

[Aging and sexuality in women]. / Invecchiamento e sessualità nelle donne.

A large number of biological, psycho-relational and socio-cultural factors are related to women's sexual health and they may negatively affect the entire sexual response cycle inducing significant changes in sexual desire, arousal, orgasm and satisfaction during the entire reproductive life span. In spite of the high prevalence of sexual problems with increasing age, sexual retirement is not an inevitable consequence of the passage of time and a high proportion of men and women remains sexually active well into later life, a result of changing attitudes toward sexuality and the availability of effective treatments for sexual dysfunction. Population-based studies reported an age-related decline of sexual functioning and an additional adverse effect of menopausal status. Ageing per se interferes with the level of sexual performance, but sexual behaviour of midlife and older women is highly dependent on several factors such as general physical and mental well-being, quality of relationship and life situation. Sex hormones, mainly low levels of estradiol, are relevant for the lack of sexual awareness and vaginal receptivity in naturally menopausal women. Even diminished levels of androgens, as it more frequently occurs in surgically menopausal women, has a negative impact on desire and sexual responsiveness. Several hormonal treatments have been used locally or systemically to alleviate sexual symptoms, especially by using estrogen plus androgen preparations and tibolone, with noticeable results on drive, enjoyment, lubrication, ability to reach orgasm and initiation of sex. However, sexual counseling and individualized management is mandatory to obtain meaningful and long-lasting results in clinical practice.

Pit and fissure sealants: results at five and ten years.

AIM: This was to evaluate the efficacy of pit and fissure sealant (FS) using two different application techniques for caries prevention assessed at five and ten years. METHODS: The study was conducted using Delton(R) pit and fissures sealant applied with either rubber dam (RD) (Group A: 50 children, 200 first permanent molars, 120 second permanent molars) or cotton wool rolls (CR) (Group B: 50 children, 200 first permanent molars, 112 second permanent molars). At five and ten years FS were evaluated for retention, loss and incidence of occlusal and proximal carious lesions recorded. STATISTICS: The data were analysed with the Chi- square test comparing the results obtained for first permanent molars and second permanent molars at five and ten years. RESULTS: There was no statistical difference between results in the two groups (p< or =0.05). The highest retention rate, 81.7%, was found for second permanent molars sealed under RD at the five year assessment. The lowest, 64.3% also for second molars sealed under CR humidity control at ten years. CONCLUSIONS: Pit and fissure sealants are a valid preventive approach that can be applied with similar results with rubber dam or cotton rolls.

Propranolol plasma levels and relief of migraine. Relationship between plasma propranolol and 4-hydroxypropranolol concentrations and clinical effects.

The relationship between propranolol and 4-hydroxypropranolol plasma concentrations and relief of migraine was assessed in 17 patients during treatment with oral racemic propranolol hydrochloride in doses of 40 to 240 mg/day. Propranolol decreased the migraine index more than 70% in 13 patients: five patients at a dosage of 40 mg/day, five patients at a dosage of 120 mg/day, and three patients at a dosage of 240 mg/day. Three patients did not achieve a good improvement of migraine at any of the doses used. The relief of migraine was not directly related to the propranolol and 4-hydroxypropranolol plasma concentrations.

Pharmacodynamic modeling of oral levodopa: clinical application in Parkinson's disease.

We investigated the relationship between levodopa plasma concentration and the tapping effect, after a standard oral levodopa test, by kinetic-dynamic modeling in 40 parkinsonian patients with stable or fluctuating response to levodopa, and found no difference in levodopa plasma pharmacokinetics between stable and fluctuating patients. Conversely, levodopa equilibration half-life between plasma and effect-site concentration was five-fold shorter on average in fluctuating patients. Overall, levodopa equilibration half-life highly correlated with the duration of tapping response and provided a reliable quantitative index of central mechanisms that affect the length of clinical effect. Individual fitting of tapping measures to modeled drug effect-site concentrations by sigmoid Emax model revealed that fluctuating patients required almost two-fold higher levodopa concentrations (EC50) to elicit almost the same motor response (Emax). These findings suggest that shortening of levodopa clinical effect may be accompanied by a reduced drug affinity for the nigrostriatal dopaminergic system (EC50), with no change in its intrinsic activity (Emax).

Longitudinal monitoring of the levodopa concentration-effect relationship in Parkinson's disease.

We prospectively evaluated over 4 years the intrasubject relationship between levodopa plasma concentration and the tapping effect after a standard oral levodopa test in 28 patients with mild-to-moderate idiopathic Parkinson's disease. The onset and duration of the tapping effect significantly shortened over years; response amplitude did not vary. Levodopa plasma kinetics remained unchanged. Pharmacodynamic modeling indicated a progressive decrease in the equilibration half-life between plasma drug concentration and effect, which correlated with the shorter motor response. No clear-cut change in maximum response (Emax) emerged, but levodopa concentration needed to yield 50% of maximum effect (EC50) significantly increased. These data indicate that the duration of motor response becomes a major determinant of drug efficacy over years. The modifications in levodopa effect-compartment equilibration half-life and EC50 further support the suggestion that alterations in cerebral levodopa kinetics have an important role in the development of response fluctuations.

Rate of motor response to oral levodopa and the clinical progression of Parkinson's disease.

We investigated the relationship between the rate of motor response after a standard levodopa oral dose and drug dynamic variables and disease-related factors in 66 patients with Parkinson's disease. Time to maximum finger tapping effect was positively correlated with matched duration of levodopa dose response and fell from a median 120 minutes in patients at Hoehn and Yahr stage I and II to 60 minutes in stage IV patients (p < 0.001). The accelerated response to levodopa dose with the advancement of disease was also apparent as an increased steepness of the tapping effect versus time curve, with a shift from a hyperbolic to a sigmoid profile. The rate of motor response to oral levodopa may reflect the rate of dopamine interaction with the postsynaptic receptors, providing an indirect objective index of presynaptic dopaminergic homeostasis.

A levodopa kinetic-dynamic study of the rate of progression in Parkinson's disease.

OBJECTIVE: The aims of the study were to follow prospectively the intrasubject progression of idiopathic PD in a cohort of patients using levodopa kinetic-dynamic modeling and to assess the relation between the rate of progression of the disease and patients' different clinical characteristics. METHODS: Thirty-four patients (Hoehn and Yahr stages 1 to 3) enrolled in the longitudinal follow-up. Each patient was examined at 1-year intervals over a median 4 years by a standardized oral levodopa test. The primary measure outcome was the computed half-life of levodopa in the "effect compartment" (t1/2eq), a proposed indicator of nigrostriatal dopaminergic functionality and integrity. RESULTS: Values of levodopa t1/2eq correlated negatively with severity of symptoms (r = -0.652, p < 0.0001) and decreased over the years together with a worsening of patients' clinical stage (p < 0.001). The rate of reduction in drug t1/2eq was more rapid in patients at the earlier stages of the disease compared with the more advanced ones, falling from a median annual reduction of 37 minutes in patients at initial Hoehn and Yahr stage 1 to 6.5 minutes in stage 3 patients (p < 0.001). Patients without tremor at onset, otherwise comparable to patients with tremor for baseline values of levodopa t1/2eq, disease severity, duration, and daily dose of levodopa, tended to show a higher rate of reduction in levodopa t1/2eq than patients with tremor. Overall, patients' annual reduction in levodopa t1/2eq over baseline values averaged 17+/-9%. CONCLUSIONS: These results are in keeping with PET findings on the objective assessment of idiopathic parkinsonism evolution, and they support the suggestion that levodopa pharmacodynamic modeling may offer a practical clinical tool to assess indirectly the functional integrity of the nigrostriatal dopaminergic system over time in parkinsonian patients.

Time-dependent interaction between phenytoin and valproic acid.

The diurnal variation in total and free plasma phenytoin (PHT) concentration at steady state was examined in eight epileptic patients receiving combination therapy with tid valproic acid (VPA) as sodium salt. Eight patients treated with PHT, but not with VPA, were studied for comparison purposes. In the absence of VPA coadministration, total and free PHT concentrations did not change significantly during the day and showed only minor intrapatient fluctuations (14 and 13%, respectively). In patients receiving VPA, the mean total PHT did not change significantly, whereas the free PHT increased during the day (p less than 0.05). The fluctuations in total and free PHT in these patients were 16 and 17% on average. In the presence of VPA, the free PHT fraction was higher than in controls (13.9 +/- 2.3% versus 8.3 +/- 1.9%; p less than 0.01) and fluctuated to a greater extent (29 versus 14% in controls; p less than 0.01), mainly as a result of combined opposite swings in both total and free concentration. The diurnal changes in free PHT concentration and fraction correlated positively with the changes in plasma VPA. An inverse relationship between total PHT concentration and plasma VPA was found in some patients. These data demonstrate that the displacement interaction between PHT and VPA is subject to diurnal variation, probably as a result of the fluctuation in plasma VPA. The implications of these findings are discussed.

Asymptomatic cores and paracrystalline mitochondrial inclusions in CADASIL.

Three siblings with genetically assessed cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with core-like lesions and mitochondrial abnormalities in muscles are described. Involvement of the Ryanodine receptor 1 gene was excluded. In the current cases, the relation between molecular genetic lesion and muscle fiber abnormalities remains to be determined, but the Notch3 gene may influence mitochondrial metabolism.

Pharmacokinetic optimisation in the treatment of Parkinson's disease.

The current symptomatic treatment of Parkinson's disease mainly relies on agents which are able to restore dopaminergic transmission in the nigrostriatal pathway, such as the dopamine precursor levodopa or direct agonists of dopamine receptors. Ancillary strategies include the use of anticholinergic and antiglutamatergic agents or inhibitors of cerebral dopamine catabolism, such as monoamine oxidase type B inhibitors. Levodopa is the most widely used and effective drug. Its peculiar pharmacokinetics are characterised by an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme aromatic-amino acid decarboxylase and rapid adsorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both drug intestinal absorption and delivery to the brain and clinical effect include standardisation of levodopa administration with respect to meal times and a controlled dietary protein intake. The levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, with swings in the therapeutic response ('wearing-off' phenomena). 'Wearing-off' phenomena can be also associated, at the more advanced disease stages with a 'negative', both parkinsonism-exacerbating and dyskinetic effect of levodopa at subtherapeutic plasma concentrations. Dyskinesias may be also related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone, and simultaneous monitoring of levodopa concentration-effect relationships may prove useful to disclose the underlying mechanism and in planning the correct pharmacokinetic management. Controlled-release levodopa formulations have been developed in an attempt to smooth out fluctuations in plasma profiles and matched therapeutic responses. The delayed levodopa absorption and lower plasma concentrations which characterise controlled-release formulations compared with standard forms must be taken into account when prescribing dosage regimens and can be complicating factors in the management of the advanced disease stages. The pharmacokinetic and pharmacodynamic characterisation of the other antiparkinsonian agents is hampered by the lack of sensitive and specific analytical methods to measure their very low plasma drug concentrations and by the difficulty in quantitatively assessing overall moderate drug clinical effects. In clinical practice an optimal dosage schedule is still generally found for each patient on an empirical basis. Future strategies should focus on the search for pharmacological agents with a better kinetic profile, particularly a higher and reproducible bioavailability and a predictable relationship between plasma drug concentration and clinical response. Treatments aimed not only at controlling the symptoms, but also at slowing the neurodegenerative process, are currently under intensive investigation.

Pharmacokinetic interactions between antiepileptic drugs. Clinical considerations.

Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial beta-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

Free concentration of carbamazepine and carbamazepine-10,11-epoxide in children and adults. Influence of age and phenobarbitone co-medication.

Total and free plasma concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) were determined in 39 children (aged 3 to 10 years) and 79 adults (aged 15 to 65 years) receiving long term treatment with CBZ alone or in combination with phenobarbitone (PB). Compared with the corresponding age groups treated with CBZ alone, adults and children receiving PB co-medication showed lower total and free CBZ concentrations, similar CBZ-E concentrations and higher CBZ-E/CBZ ratios. Among patients on CBZ alone, children had at any given dose lower total and free CBZ and CBZ-E concentrations than adults. Lower CBZ levels in children than in adults were also found among patients receiving phenobarbitone in combination. CBZ-E/CBZ ratios did not differ significantly between children and adults. These data provide evidence that children show an elevated free CBZ clearance with a metabolic pattern different from that observed during phenobarbitone induction.

Effects of acute valproic acid administration on carnitine plasma concentrations in epileptic patients.

Serial plasma samples collected after an acute administration of valproic acid, (VPA, 15 mg/kg as oral solution) in epileptic patients were selected for this study. The plasma samples were selected from three different groups of patients; patients on phenobarbital and phenytoin with clinical VPA intolerance (group A); patients on phenobarbital and phenytoin without clinical VPA toxicity (group B); and patients without phenobarbital and phenytoin and without clinical VPA toxicity (group C). Plasma samples from 6 patients per group were analyzed for carnitines and ammonia. Ammonia levels during acute study increased significantly (P less than 0.05) in patients who experienced VPA intolerance, while no changes were found in the other patients. After acute VPA administration, total carnitine was unchanged but free carnitine was decreased (P less than 0.05) and carnitine esters were increased (P less than 0.05) in all groups of patients studied. No difference in carnitine profiles was seen between patients with or without evidence of VPA administration has an important effect on carnitine metabolism. However, unlike the acute effect on ammonia metabolism, this acute effect does not seem to be correlated with any associated antiepileptic therapy, nor does it predict clinical VPA intolerance.

Predictive performance of pharmacokinetic methods for phenytoin dosing: a multi-center evaluation in 282 patients with epilepsy.

A retrospective study was conducted in 282 patients with epilepsy to assess the predictive performance of pharmacokinetic methods for individualizing dosage of phenytoin. Two population-based dosing methods (population clearance method and bayesian feedback method) and one individual-based method (the so-called linearized Michaelis-Menten method) were evaluated, when applicable, for single-point and/or 2-point dose predictions of phenytoin. In single-point predictions, we found a generally low percentage of dose calculations falling inside the +/- 10% range (48.9% and 51.1% for the population clearance and the bayesian methods, respectively). In 2-point predictions, the bayesian method was 'accurate' (dose within the +/- 10% range) in approximately 54.3% or 55.0% of cases (depending on the particular method of implementation adopted). An even worse percentage of 'accurate' dose predictions (38.3%) was obtained by using the linearized Michaelis-Menten method. Our data do not confirm results from previous studies indicating a generally good performance of pharmacokinetic methods for predicting phenytoin dosage.

No effect of chronic bromocriptine therapy on levodopa pharmacokinetics in patients with Parkinson's disease.

We studied the effect of chronic bromocriptine cotherapy on levodopa kinetics in seven patients with Parkinson's disease who were receiving levodopa therapy. Plasma levodopa concentrations were measured after a standard oral levodopa fasting dose over a 5-hour period, on two different sessions, without and with bromocriptine at a fixed daily dose of 15 mg. We found no statistically significant difference in the rate and extent of levodopa absorption between the two treatments, with minimal intrasubject variability. Our observations suggest that chronic bromocriptine cotherapy is unlikely to affect the plasma levodopa pharmacokinetics under standardized intake conditions or to contribute to a less predictable pattern of drug plasma concentrations.