Investigation of injectable drug utilization in primary care: A focus on different age groups in pediatric population.

OBJECTIVE: The suitability of the injectables may vary across different age groups especially for children; therefore, knowledge on their usage patterns is critical in terms of rational pharmacotherapy. This study aimed to investigate pediatric injectable drug utilization in primary care with a focus on different age groups. METHOD: By simple sampling method, 100 prescriptions that contained at least one injectable drug were randomly selected for each month of the year in 32 provinces of Turkey (n=38.400). Among these prescriptions, injectable drugs that were for children (<18 years) were analyzed. Patterns of injectable drug utilization were compared according to the pediatric age group of "infants", "children", and "adolescents". RESULTS: We identified 5446 patients (14.2%) with a mean age of 7.4±5.2 years and a slight male tendency in distribution (53.8%). The most common indication for these patients was for the respiratory system (65.4%), of which 96.3% were respiratory tract infections. While less pronounced in adolescents than in infants and children, the most commonly prescribed injectable drugs were antibiotics in all age groups (61.5% vs. 78.6% and 79.9%, P<0.0001), which was upheld across all seasons. More than 90% of all prescribed injectable antibiotics consisted of penicillins and cephalosporins; the latter being predominant in infants (67.4%) compared with penicillins in children (53.9%) and adolescents (59.0%). Analgesics and insulin were found to be prescribed more frequently to adolescents than they were to infants and children (P<0.0001 and P<0.0001, respectively). The mean cost of prescription and injectable drugs per encounter was significantly more likely to escalate with increasing age (P<0.0001 and P<0.0001, respectively). CONCLUSION: Considering the predominance of antibiotics as well as the substantially higher prescription of third-generation cephalosporins in primary care, which was especially more marked for younger children, our study indicates an inappropriate use of injectable drugs by primary care physicians for managing medical conditions in the pediatric population.

Drug utilization and potentially inappropriate drug use in elderly residents of a community in Istanbul, Turkey.

OBJECTIVE: This study investigates drug utilization and estimates the prevalence of potentially inappropriate drug use in a Turkish population aged 70 years or older. MATERIAL AND METHODS: A cross-sectional study was carried out on a total of 1019 participants who accepted face-to-face questionnaires in home interviews in Istanbul. All medications used in the three weeks prior to the study were recorded. Some major risk factors that might influence the use of inappropriate medication such as socio-demographic characteristics and concomitant disease such as depression and dementia were also questioned. Inappropriate drug use was assessed using the Beers criteria. RESULTS: Among the 1019 participants, 903 (88.6%) had been using at least one medication during the last three weeks. The average number of medications used was 2.9 +/- 2.0. The most frequently drugs used were cardiovascular drugs (39.9%), followed by analgesics/anti-inflammatory drugs (16.2%), vitamin/mineral preparations (10.6%) and central nervous system drugs (10.2%). Of the 1,019 participants, 9.8% were using one potentially inappropriate medication and one patient was using two inappropriate drugs. The most common of these drugs were reserpine (23.7%), dipyridamole (21.8%), antihistamines (14.8%), and benzodiazepines (10.9%). Only age and total number of medications were associated with potentially inappropriate drugs in the multivariate analysis. CONCLUSIONS: This study revealed that drug utilization and the prevalence of inappropriate medication use in the elderly were lower than in published reports from most developed countries. Furthermore, polypharmacy and higher age were the main risk factors for potentially inappropriate drug use in the elderly.

NK-1 antagonist CP99994 inhibits stress-induced mast cell degranulation in rats.

Mast cells are implicated in stress-induced inflammatory skin diseases such as psoriasis. Mechanisms of stress-induced mast cell degranulation however, are not entirely clear. Here we explore the role of activation of a Substance P (SP) receptor (NK-1) on mast cell degranulation upon exposure to stress in rats. A specific nonpeptide NK-1 antagonist, CP99994 was used to treat the rats either peripherally or intracerebroventricularly. Because increased SP activity in the brain may mediate the stress response, we also examined cutaneous mast cell degranulation after central injection of SP. Stress, as well as SP injected centrally, increased mast cell degranulation. Both central and peripheral injection of CP99994 prevented stress-induced mast cell degranulation. Surprisingly, the combination of stress with SP decreased mast cell degranulation, suggesting that high levels of SP may counteract the stress responses. Results in this animal model suggest that NK-1 antagonists may be used therapeutically to treat stress-induced inflammatory skin diseases; however, drug doses should be chosen carefully.

Comparison of rational pharmacotherapy decision-making competence of general practitioners with intern doctors.

OBJECTIVE: The aim of this study was to compare rational pharmacotherapy decision-making competency of interns (final-year medical students) who had received rational pharmacotherapy education (RPE), with their classmates at another medical school and general practitioners (GPs) who had not been exposed to RPE. DESIGN: A written, objective, structured clinical examination (OSCE), consisting of open and structured questions, was given to all participants. The participants were expected to make a treatment plan and prescribe for simple, uncomplicated beta-hemolytic streptococcal tonsillitis and mild-to-moderate essential hypertension patients, explain their proposed treatment plans and reasons affecting their drug choice. After the OSCE, a questionnaire to assess knowledge of the rational use of drugs was given to the participants. RESULTS: Fifty RPE(+) interns, 54 RPE(-) interns and 53 GPs participated in the study. Mean scores of RPE(+) interns were higher than those of GPs, which were in turn found to be higher than those of RPE(-) interns for all cases. The RPE(+) interns scored the highest regarding all components of rational pharmacotherapy process for all cases of both indications. However, participants in all groups had higher scores for the structured questions compared with the corresponding open ones for both diseases. Prescription analysis also revealed better results for RPE(+) interns regarding the number of drugs/prescription and treatment costs. CONCLUSION: The present study demonstrated that the final-year medical students (interns) markedly benefited from undergraduate RPE at the medical school in developing rational prescribing skills compared with their classmates from a medical school with traditional pharmacology education. Interestingly, they got higher scores than not only RPE(-) interns, but also than the GPs participating in this study, indicating the urgent need for continuous medical education programs in this field throughout the country for practicing GPs.

What do graduates think about a two-week rational pharmacotherapy course in the fifth year of medical education?

The present study aims to assess the short- and mid-term post-graduation impact of a pharmacotherapy course in the fifth year at Marmara University School of Medicine by an objective (OSCE) and a subjective (questionnaires) evaluation. Statistical comparison of pretest, posttest-exposed case and posttest-unexposed case scores indicated both a retention and a transfer effect of training. The post-course questionnaire revealed that 95%of the students found the course useful and necessary; 97% reported that they will apply a rational pharmacotherapy approach using this model and communicate better with their patients. The post-graduation questionnaire also showed that the majority of them have learned general principles of rational pharmacotherapy(90%), gained good prescribing (90%) and communication skills (87.5%), and understood the importance of non-pharmacological treatment alternatives (100%). In general, they stated that they would apply the principles during their medical practice and they believed their colleagues would do too. In conclusion, the present study demonstrates the benefit of a clinical pharmacology programme focused on rational pharmacotherapy during the clinical years of medical education.

The role of nitric oxide in the reversal of hemorrhagic shock by oxotremorine.

In the present study, the effect of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methylester (L-NAME), on the antishock actions of oxotremorine was investigated in rats subjected to hemorrhagic shock under urethane anesthesia. L-citrulline production in the AV3V region, as an indicator of nitric oxide (NO) synthesis, was assayed by high-performance liquid chromatography (HPLC) with fluorescent detection throughout the experiment. The rats were pretreated with either intravenous (i.v.) physiological saline or L-NAME (2.5 mg/kg) before bleeding. L-NAME potentiated the reversal of hypotension by oxotremorine (25 microg/kg, i.v.). However, oxotremorine either alone or in combination with L-NAME did not produce any significant change in 60-min survival rate at this low dose. Analysis of microdialysis samples collected from the AV3V region showed that L-citrulline concentration increased during bleeding and that this increase was abolished by L-NAME pretreatment. These results may suggest that nitric oxide production contributes to hypotension in rats bled to shock since nitric oxide levels in the AV3V region increased in response to bleeding and nitric oxide synthase (NOS) inhibition abolished this increase and potentiated the oxotremorine-induced reversal of hypotension.

Cardiovascular responses to NMDA injected into nuclei of hypothalamus or amygdala in conscious rats.

The nuclei of hypothalamus and amygdala have been shown to be involved in the central cardiovascular homeostasis. Recent studies suggest that glutamate-containing neurons have an important role in the regulation of the central cardiovascular function. In this study, we demonstrate the roles of the central nucleus of the amygdala and the paraventricular nucleus of the amygdala and the paraventricular nucleus or the dorsomedial nucleus of the hypothalamus in N-methyl-D-aspartate (NMDA) induced blood pressure and heart rate changes in conscious Sprague-Dawley rats. Intracerebroventricular or parenchymal injections of NMDA evoke increases in arterial pressure. The NMDA-induced elevations in blood pressure are more prominent when NMDA is administered into the dorsomedial nucleus of the hypothalamus. Microinjections of NMDA into the dorsomedial hypothalamus exert significant heart rate increases, whereas NMDA when administered into the paraventricular nucleus of the hypothalamus or into the central nucleus of the amygdala has no significant effect on the heart rate. The dorsomedial nucleus of the hypothalamus is found to be the most effective site in this respect. The present study provides strong evidence for the tonic glutamatergic influence on blood pressure and heart rate via NMDA receptors located within the dorsomedial nucleus and to a lesser extent via those located within the paraventricular nucleus of the hypothalamus.

Further evidence for the heterogeneity of functional muscarinic receptors in guinea pig gallbladder.

Previous studies have suggested the presence of multiple muscarinic receptor subtypes in guinea pig gallbladder smooth muscle, although the relative abundance and functional role of these subtypes remains an area of significant research efforts. The present study utilized both radioligand kinetic and functional experiments to further probe the nature of the muscarinic receptors in gallbladder smooth muscle and their mode of coupling to intra- and extra-cellular Ca(2+) sources. Dissociation kinetic studies using [3H]N-methylscopolamine ([3H]NMS) indicated that the binding profile in guinea pig gallbladder smooth muscle could not be reconciled with that expected for a single muscarinic receptor subtype, the latter determined in parallel experiments conducted on the cloned muscarinic M(1)-M(5) subtypes in Chinese hamster ovary (CHO) cells. Furthermore, comparison of the gallbladder data with the dissociation characteristics of [3H]NMS in guinea pig urinary bladder revealed a significantly different kinetic profile, with the urinary bladder, but not the gallbladder, demonstrating biphasic radioligand dissociation kinetics. In functional experiments, carbachol caused a concentration-dependent contraction of guinea pig gallbladder smooth muscle strips in Ca(2+)-free or 5 mM Sr(2+)-substituted physiological salt solutions (PSS) with amplitudes of the maximal contractions corresponding to 45.8+/-8.0% and 33.2+/-6.6% of control responses in normal PSS, respectively. Furthermore, the stimulus-response characteristics of carbachol-mediated contraction appeared significantly altered in Ca(2+)-free PSS relative to normal or Sr(2+)-substituted PSS. The antagonist, methoctramine (1x10(-7)-3x10(-5) M), exerted only a slight inhibition of carbachol (10(-5) M)-induced contractions in 5 mM Sr(2+)-substituted medium, whereas it was significantly more potent in antagonizing gallbladder contractions in response to 10(-5) M carbachol in the absence of extracellular Ca(2+). Both atropine and tripitramine were equipotent in antagonizing carbachol-induced contractions in Ca(2+)-free (pIC(50): 6.85+/-0.11 for atropine and 5.75+/-0.32 for tripitramine) and Sr(2+)-substituted media (pIC(50): 6.88+/-0.25 for atropine and 5.70+/-0.16 for tripitramine), and pirenzepine was only slightly more potent in Ca(2+)-free PSS (pIC(50): 5.66+/-0.23) than in Sr(2+)-substituted PSS (pIC(50): 5.33+/-0.21). Taken together, our data indicate that carbachol contracts guinea pig gallbladder by stimulating two distinct muscarinic receptor subtypes linked to extracellular Ca(2+) influx and intracellular Ca(2+) release. These two subtypes may represent the muscarinic M(3) and M(4) receptors, although the presence of the muscarinic M(2) receptor subtype is also suggested from the binding data.

Muscarinic M(2) receptors are not primarily involved in the contraction of guinea-pig gallbladder smooth muscle.

The presence of M(1)-M(4) receptors in guinea-pig gallbladder smooth muscle cells has been reported recently. The majority of these receptors are said to be of M(2) subtype. However, there are controversial reports about the functional muscarinic receptors that mediate contraction in this tissue. Similar to gallbladder, it was claimed that M(4) receptors mediate guinea-pig uterine contractions, but these receptors have appeared to be of M(2) subtypes later. Therefore, the antagonistic affinities of three M(2)-selective muscarinic antagonists were determined in contraction and radioligand binding experiments in guinea-pig gallbladder in the present study. The antagonistic affinity values (p K(i)) of gallamine, tripitramine and imperialine were as follows, respectively: 6.28+/-0.15, 8.65+/-0.10 and 6.55+/-0.07 against 0.250 n m [(3)H]QNB binding. All three antagonists displaced the concentration- response curves to carbachol to the right in parallel without affecting the maximum responses. The p A(2) values obtained from constrained Schild plots (-log K(B)) were 4.14+/-0.18 for gallamine, 6.79+/-0.09 for tripitramine, and 7.02+/-0.09 for imperialine. The antagonistic affinity values of gallamine, tripitramine and imperialine for M(2) receptors are reported to be 6. 3, 9.6, 7.7, respectively. The p A(2) values obtained in this study clearly indicate that the primary muscarinic receptors involved in carbachol-induced guinea-pig gallbladder contraction are not of M(2) subtype. The poor correlation between the antagonistic affinity values of these antagonists obtained at radioligand binding (p K(i)) and contraction (p A(2)) experiments also support the conclusion that the majority of muscarinic receptors which have been reported to be of M(2) do not mediate the contractile responses.

Distinct functional muscarinic receptors in guinea-pig gallbladder, ileum and atria.

OBJECTIVE: The contractile responses of guinea-pig gallbladder smooth muscle cells have been suggested to be mediated by M3 and M4 muscarinic receptors by different research groups. Therefore, in the present study, several pharmacological properties of cholinergic functions in guinea-pig gallbladder, guinea-pig ileum (mediated via M3 receptors), and guinea-pig and rat atria (mediated via M2 receptors) were compared. METHODS: The isometric contractions of isolated guinea-pig ileum, guinea-pig gallbladder, guinea-pig and rat atrial strips in in vitro organ bath were recorded on a polygraph and the effects of carbachol, oxotremorine, McN-A-343, and clozapine have been investigated. RESULTS: Three muscarinic receptor agonists, carbachol, oxotremorine and McN-A-343 showed different order of potencies in their negative inotropic effects and contractile actions in guinea-pig gallbladder suggesting that functional muscarinic receptors in the gallbladder are distinct from those in the atria, and similar to M4-subtypes. Clozapine which was shown to have antagonistic affinity for muscarinic M1, M2, M3 and M5, but partial agonistic affinity for muscarinic M4 receptors, contracted gallbladder concentration-dependently. On the other hand, clozapine antagonised carbachol-induced ileal and gallbladder contractions and negative inotropic effects indicating that it acts like a partial agonist in the gallbladder. CONCLUSION: It was concluded that the contractile muscarinic receptors of guinea-pig gallbladder are distinct from those of atria (M2) and ileum (M3), but seem to be of M4 subtype.