Health Resource Utilisation and Disparities: an Ecological Study of Admission Patterns Across Ethnicity in England Between 2017 and 2020.

BACKGROUND AND AIM: The COVID-19 pandemic highlighted adverse outcomes in Asian, Black, and ethnic minority groups. More research is required to explore underlying ethnic health inequalities. In this study, we aim to examine pre-COVID ethnic inequalities more generally through healthcare utilisation to contextualise underlying inequalities that were present before the pandemic. DESIGN: This was an ecological study exploring all admissions to NHS hospitals in England from 2017 to 2020. METHODS: The primary outcomes were admission rates within ethnic groups. Secondary outcomes included age-specific and age-standardised admission rates. Sub-analysis of admission rates across an index of multiple deprivation (IMD) deciles was also performed to contextualise the impact of socioeconomic differences amongst ethnic categories. Results were presented as a relative ratio (RR) with 95% confidence intervals. RESULTS: Age-standardised admission rates were higher in Asian (RR 1.40 [1.38-1.41] in 2019) and Black (RR 1.37 [1.37-1.38]) and lower in Mixed groups (RR 0.91 [0.90-0.91]) relative to White. There was significant missingness or misassignment of ethnicity in NHS admissions: with 11.7% of admissions having an unknown/not-stated ethnicity assignment and 'other' ethnicity being significantly over-represented. Admission rates did not mirror the degree of deprivation across all ethnic categories. CONCLUSIONS: This study shows Black and Asian ethnic groups have higher admission rates compared to White across all age groups and when standardised for age. There is evidence of incomplete and misidentification of ethnicity assignment in NHS admission records, which may introduce bias to work on these datasets. Differences in admission rates across individual ethnic categories cannot solely be explained by socioeconomic status. Further work is needed to identify ethnicity-specific factors of these inequalities to allow targeted interventions at the local level.

Gestational trophoblastic neoplasia presenting as an interstitial ectopic pregnancy.

Gestational trophoblastic disease (GTD) is a group of benign and malignant tumors that develop from placental tissue and includes hydatidiform moles and gestational trophoblastic neoplasia (GTN). Invasive molar disease and choriocarcinoma are rare forms of GTN and can arise from any pregnancy event. An interstitial ectopic pregnancy occurs with implantation within the intramural portion of the fallopian tube covered by myometrium. We present two cases of an invasive mole with pathology consistent with choriocarcinoma in situ arising from an interstitial ectopic pregnancies. We review management strategies including a minimally invasive surgical approach. Additionally we present a review of the literature of gestational trophoblastic disease associated with interstitial ectopic pregnancies.

Differences in bioavailability between 60 mg of nifedipine osmotic push-pull systems after fasted and fed administration.

OBJECTIVES: This study was designed to evaluate and compare the bioavailability of two osmotically active formulations of 60 mg nifedipine, Gen-Nifedipine extended release Test tablets (Genpharm ULC, Etobicoke, ON, Canada) and Adalat XL Reference tablets (Bayer Healthcare AG, Leverkusen, Germany) after single dose fasted and fed administration. MATERIALS AND METHODS: The study was performed following a 4-period crossover design with both investigational products obtained from marketed batches. The complete pharmacokinetic evaluation was carried out in 26 healthy male subjects with a median age of 29.5 years (range 18 - 44 years), mean weight of 79.7 kg (range 66.0 - 97.5 kg), and a mean body mass index (BMI) of 24.1 kg/m(2) (range 22.1 - 26.9 kg/m(2)). Tablets were administered with tap water either under fasting conditions or immediately following a high-fat, high-calorie breakfast. Blood samples were taken predose and at pre-defined time points until 48 h post dosing. Samples were protected from light during handling and frozen until analysis. A validated LC-MS/MS method was used for the quantification of nifedipine in plasma samples. All kinetic parameters were determined model-independently for each treatment directly from measured concentrations. Monitoring of subject safety was accomplished by routine monitoring of blood pressure, heart rate and probing for adverse events. RESULTS: In-vitro dissolution curves show later onset and considerably lower quantity of nifedipine release from Test compared to Reference tablets. Under fasting conditions total and maximum exposure, represented by geometric mean AUC(0-tlast)- and C(max)-values, respectively were 466.7 h*ng/ml (AUC(0-tlast)) and 21.9 ng/ml (C(max)) for Test and 507.8 h*ng/ml (AUC(0-tlast)) and 22.0 ng/ml (C(max)) for Reference tablets. However, the Test product exhibited a notably longer lag-time and less rapid onset of absorption than the Reference tablets. Moreover, the plateau phase is maintained for about 14 hours on Test but for almost 20 hours on Reference. Point estimates (PE) and associated 90% confidence intervals (CI) were determined as 91.8% and 79.9 - 105.5% for AUC(0-tlast), as well as 99.8% and 88.6 - 112.4% for C(max). Larger differences were found for AUC(0-9h) (PE: 54.8%; CI: 45.8 - 65.5%) determined as parameter for early exposure. Under fed conditions, although the mean plasma concentration time curves look similar in shape, concentrations of Test compared to Reference tablets are considerably lower at all time points until 36 hours after dosing. Again the lag time in onset of drug absorption is notably longer for the Test product. Both, total and maximum exposure, represented by geometric mean values for AUC(0-tlast) and C(max), were considerably lower (differences also statistically significant) after administration of Test with 481.8 h*ng/ml for AUC(0-tlast) and 25.3 ng/ml for C(max) in comparison to Reference tablets with 595.9 h*ng/ml for AUC(0-tlast) and 31.9 ng/ml for C(max). Test/Reference point estimates (PE) and associated 90% confidence intervals (CI) were determined as 80.7% and 73.7 - 88.5% for AUC(0-tlast), as well as 79.6% and 70.3 - 90.0% for C(max). Differences were also even more expressed for AUC(0-9h) (PE: 54.9%; CI: 47.4 - 63.5%) determined as parameter for early exposure. CONCLUSION: The results indicate that although both products are osmotic release systems they are not bioequivalent according to the accepted standards. This difference between both osmotic delivery systems might be substantiated by the fact that the core of the Test product is designed as a monolayer system (containing both, the active ingredient and the osmotic component) while Reference tablets consist of two separate layers. The observed pharmacokinetic differences may have an impact on blood pressure control in patients and thus, should be kept in mind when switching during treatment.

The clinical utility of the test of playfulness.

Occupational therapists' increased focus on play as an occupation has created a need for play assessments that reflect this perspective. This study examined the clinical utility of the recently developed Test of Playfulness (ToP) (Bundy, 1997a) when used with children with disabilities. Changes in the participant's views of the child, the therapy goals, and the intervention plans after using the ToP were explored. Fourteen paediatric occupational therapists assessed children using the ToP, completed a clinical utility questionnaire and attended a focus group. Participants found the ToP easy to administer and score, however some found interpreting the results difficult. The ToP highlights the interactions between the Child, activity and environment, and illustrates the child's strengths in his/her role as a player. The results suggest the ToP is a useful tool for assessing playfulness. Additional education and research is needed to provide further direction for intervention and incorporation into practice.

Blood pressure control in patients with mild to moderate essential hypertension switched from nifedipine gastrointestinal therapeutic system (GITS) 30 mg to nifedipine GITS 20 mg.

BACKGROUND: Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides sustained plasma nifedipine concentrations throughout the 24-hour dosing interval. OBJECTIVE: This study was undertaken to determine if adult patients with mild to moderate essential hypertension whose blood pressure had been controlled for > or = 3 months with nifedipine GITS 30 mg could be successfully switched to a 20-mg daily dose with continued antihypertensive efficacy. METHODS: This was a randomized, double-blind, parallel-group study. Patients entered a 1-week run-in period during which they continued to receive their usual antihypertensive medication, including nifedipine GITS 30 mg. After baseline assessment, patients entered a 6-week treatment period during which they were randomly assigned to receive nifedipine GITS 30 or 20 mg. Men and women were eligible to participate if they were > or = 55 years of age, had received a diagnosis of mild to moderate essential hypertension (sitting diastolic blood pressure [DBP] 95-114 mm Hg), and had exhibited good blood pressure control (sitting DBP < or = 90 mm Hg) while taking nifedipine GITS 30 mg once daily for > or = 3 months. Systolic blood pressure (SBP), DBP, and heart rate were recorded at baseline and after 1, 3, and 6 weeks of treatment. Adverse events were reported by patients. The responder rate was defined as the percentage of patients whose sitting DBP was < 95 mm Hg at the final study assessment. Results were based on the intent-to-treat analyses, which included data for all patients who received > or = 1 dose and had 1 postbaseline blood pressure assessment. Statistical significance was set at P < 0.05. RESULTS: Seventy-five patients entered the 1-week run-in period; 71 patients (94.7%) were randomized to treatment. Twenty-four patients received nifedipine GITS 30 mg for 43.0 +/- 3.3 days, and 47 patients received nifedipine GITS 20 mg for 42.5 +/- 6.7 days. Both groups exhibited a sustained decrease in blood pressure throughout the study; minor variations were not statistically significant. End-point SBP and DBP for the 30- and 20-mg groups were 135.5 +/- 9.8/81.7 +/- 5.4 mm Hg and 138.6 +/- 11.8/82.9 +/- 7.6 mm Hg, respectively. Changes from baseline in end-point SBP and DBP did not differ significantly between groups. At the end of treatment, goal DBP (< 95 mm Hg) was achieved by 24 of 24 patients (100%) receiving the 30-mg dose and 45 of 47 patients (95.7%) receiving the 20-mg dose. Blood pressure control (sitting DBP < 90 mm Hg) was achieved by 21 of 24 (87.5%) patients in the 30-mg group and 35 of 47 (74.5%) patients in the 20-mg group. The most commonly reported adverse event was headache; 2 patients discontinued the study because of adverse events. Overall, 9 of 24 patients (37.5%) in the 30-mg group and 14 of 47 patients (29.8%) in the 20-mg group experienced > or = 1 treatment-related adverse event. CONCLUSIONS: Patients whose mild to moderate essential hypertension is controlled with nifedipine GITS 30 mg once daily may be able to switch to 20 mg once daily with continued antihypertensive efficacy. In addition to safety and economic advantages, such a switch may be a reasonable alternative in patients with lower body weight or as an adjunct to existing antihypertensive therapy.

Effectiveness of nifedipine GITS in combination with atenolol in chronic stable angina.

Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides stable plasma concentrations over the entire 24 h dosing interval. Two-hundred and one patients with Canadian Cardiovascular Society class II to III angina who were on 50 mg of atenolol yet still experiencing angina symptoms were randomized to receive either placebo or nifedipine GITS 30, 60 or 90 mg/day. After four weeks of treatment, the changes in time from baseline to onset of 1 mm ST segment depression in the 183 eligible patients were 26.7+/-10.2 s, 40.9+/-11.3 s, 63.2+/-12.9 s and 70.3+/-12.6 for the placebo, and 30, 60 and 90 mg/day groups, respectively. These differences were significant (P<0.05) for the 60 and 90 mg/day groups compared with placebo and for the 60 mg/day group compared with the 30 mg/day group. The times to onset of pain and termination of exercise showed similar prolongation but did not achieve statistical significance. During the one-year open label phase of the study, patients exhibited statistically significant improvements in the time to onset of ST segment depression, time to anginal pain and time to termination of exercise at a mean dose of 52.3 mg/day of nifedipine GITS. Adverse events were primarily vasodilatory in nature. This study supports the use of nifedipine GITS in patients with chronic stable angina inadequately controlled on beta-blocker alone.

Effects of antihypertensive therapies on the sympathetic nervous system.

The sympathetic nervous system is a major modulator of cardiovascular function. Over the past three decades, numerous studies, using various methodologies, have reported the existence of a variety of pre- and postsynaptic sympathetic dysfunctions in essential hypertension. Most of these abnormalities facilitate sympathetic neurotransmission, resulting in a chronic increase in the sympathetic tone and reactivity in a significant proportion of hypertensive patients. Chronic sympathetic activation is also associated with major alterations in the balance among postsynaptic adrenergic receptors in cardiovascular tissues. Indeed, an attenuation of beta-adrenergic function and a potentiation of alpha1-adrenergic function has been demonstrated in cardiovascular tissues in hypertensive patients, suggesting the development of a sympathetic postsynaptic alpha1 dominance during the development and evolution of hypertension. Chronic activation of the sympathetic system is deleterious and could contribute to the development of most cardiovascular complications associated with hypertension. One of the major aims of antihypertensive therapy should thus be to attenuate pre- or postsynaptic sympathetic tone. Most antihypertensive drugs have been found to improve either pre- or postsynaptic sympathetic function in hypertensive patients. At the presynaptic level, diuretics were found to increase the liberation of noradrenalin, presumably through baroreflex sympathetic activation. In contrast, beta-blockers were shown to attenuate noradrenalin release from sympathetic nerves by blocking presynaptic facilitatory beta-receptors, thus reducing the sympathetic tone on postsynaptic receptors. Similarly, angiotensin-converting enzyme inhibitors or angiotensin II type 1 (AT1) receptor antagonists have been found to reduce sympathetic reactivity by acting on the central nervous system, but also by blocking AT1-mediated facilitatory mechanisms located on sympathetic fibres and in the adrenal medulla. Short acting dihydropyridine calcium channel blockers (CCBs) were found to enhance noradrenalin release from sympathetic nerves, but longer acting CCBs seems to have variable effects. Indeed, while the chronic slow release formulation of nifedipine gastrointestinal therapeutic system (GITS) did not raise circulating noradrenalin levels, treatment with amlodipine increased circulating noradrenalin levels, suggesting that nifedipine GITS is neutral on the sympathetic tone but that amlodipine chronically activates the sympathetic system. At the postsynaptic level, however, dihydropyridine CCBs were shown to attenuate the sympathetic tone on alpha1-adrenoceptors. In conclusion, it appears that most antihypertensive drugs interfere with pre- or postsynaptic sympathetic mechanisms and that these mechanisms could contribute to their hypotensive effects.

Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.

OBJECTIVE: To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). DESIGN AND METHODS: After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. RESULTS: Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). CONCLUSIONS: The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.

Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.

OBJECTIVE: To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). DESIGN AND METHODS: After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. RESULTS: Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). CONCLUSIONS: The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.

Efficacy of a low dose nifedipine GITS (20 mg) in patients with mild to moderate hypertension.

Nifedipine gastrointestinal therapeutic system (GITS) is a once-a-day formulation of nifedipine providing stable plasma concentrations over the entire 24 h dosing interval. The antihypertensive efficacy of a new 24 mg formulation was evaluated in 187 patients in 15 centres across the country. After a two-week placebo washout, mild to moderate hypertensive patients were randomized in a double-blind, parallel design to four weeks of placebo or nifedipine GITS 20 mg once daily treatment. Changes in office blood pressure (BP) were noted for each group. Ambulatory BP was also monitored at baseline and after four weeks of placebo/nifedipine therapy in a subgroup of 66 patients at five centres. After four weeks of treatment, office BP in the placebo group decreased by 5.0 +/- 11.9/5.4 +/- 7.9 mmHg compared with 9.3 +/- 11.2/8.6 +/- 7.4 mmHg in the nifedipine GITS group. Both systolic and diastolic BP were significantly decreased (P = 0.006 and P = 0.001 for systolic and diastolic, respectively) more with nifedipine GITS. Heart rate did not significantly differ between the groups at baseline nor after four weeks of treatment. The percentage of responders--defined as having a sitting diastolic BP less than 90 mmHg or a decrease from baseline of 10 mmHg--was 57% for nifedipine GITS versus 32% for placebo (P < 0.05). Daytime average diastolic blood pressure was 86.4 +/- 6.4 mmHg in the nifedipine GITS 20 mg group compared with 93.7 +/- 8.9 mmHg in the placebo group (P < 0.02). The maximum antihypertensive effect of nifedipine during ambulatory monitoring was similar to the reduction in BP observed in the office at the end of the dosing interval. The frequency of spontaneously reported adverse events was similar for nifedipine GITS (32.3%) and placebo (37.2%). These results indicate that 20 mg of nifedipine GITS is efficacious in decreasing BP, with good 24 h control and an incidence of adverse events similar to that of placebo-treated patients.

Nifedipine gastrointestinal therapeutic system (GITS) for hypertensive patients in a primary care setting: results of the Extended Release Adalat Canadian Trial (EXACT).

Nifedipine gastrointestinal therapeutic system (GITS) is an extended-release dosage formulation that provides sustained blood concentrations of nifedipine over 24 hours. A 20-week, postmarketing surveillance study of the effectiveness and patient tolerability of nifedipine GITS 30 or 60 mg was conducted in the offices of 187 Canadian general practitioners from September 1992 to March 1994. A total of 1700 patients previously or newly diagnosed with mild-to-moderate essential hypertension (sitting diastolic blood pressure, 95 to 114 mm Hg) were included. The 20-week treatment period was completed by 1326 patients. Patients received nifedipine GITS 30 mg initially; the dose could be titrated upward to 60 mg after 3 and 6 weeks. Of all patients entered, 605 (35.6%) reported one or more adverse events. The three most frequently occurring adverse events were headache (12.2%), peripheral edema (8.1%), and dizziness (2.9%). The frequency of adverse events was highest in the first 3 weeks and decreased subsequently. The overall incidence of adverse events was 29.8% in patients receiving 30 mg of nifedipine GITS and 25.3% in those receiving 60 mg; adverse events were the cause of study discontinuation in 12.3% of patients. The overall health status of patients as measured by the SF-36 questionnaire was comparable to that previously reported for healthy individuals. At baseline, mean (+/- SE) systolic/diastolic blood pressure values for all patients were 160.1 +/- 0.4/97.4 +/- 0.2 mm Hg. Final blood pressure readings after 20 weeks of treatment in the 30-mg group (141.5 +/- 0.4/84.8 +/- 0.2 mm Hg) and the 60-mg group (146.6 +/- 0.8/88.8 +/- 0.4 mm Hg) were significantly decreased from baseline. At week 20, the 30-mg dose was sufficient to maintain blood pressure in 74.5% of patients; 25.5% of patients required 60 mg. Subgroup analysis revealed similar responses in patients who had received blood pressure medication before study initiation and those who had not. Response was also independent of age and type of previous antihypertensive therapy. In general medical practice, the 30-mg and 60-mg doses of nifedipine GITS were both effective and well tolerated and had minimal or no negative effects on the overall health status of treated individuals.

Comparative efficacy of two long-acting formulations of nifedipine in the treatment of hypertension. The Switch Study Investigators.

OBJECTIVE: To compare the antihypertensive effects and incidence of side effects of two formulations of nifedipine: a prolonged action (PA) tablet bid and a gastrointestinal therapeutic system (GITS) tablet once daily. DESIGN: Patients with controlled hypertension (diastolic blood pressure less than 90 mmHg) on nifedipine-PA 10 mg (n = 74) or 20 mg (n = 99) bid were enrolled into an open label study consisting of six weeks of previous nifedipine-PA followed by six weeks of nifedipine-GITS therapy. Nifedipine-GITS was increased from 30 mg to 60 mg daily if the patient's diastolic blood pressure increased by at least 10 mmHg compared with the value after six weeks of nifedipine-PA. MAIN RESULTS: Blood pressure after six weeks of nifedipine-PA 10 mg (142 +/- 1/86 +/- 1 mmHg) decreased (P < 0.01) after conversion to nifedipine-GITS 30 mg (137 +/- 1/84 +/- 1 mmHg). Blood pressure values for nifedipine-PA 20 mg patients were unchanged after conversion to nifedipine-GITS; 74 patients received nifedipine-GITS 30 mg and 14 patients required titration up to nifedipine-GITS 60 mg daily. Sixteen patients withdrew on nifedipine-PA and five withdrew on nifedipine-GITS, mostly for reasons unrelated to drug therapy. Twenty-three patients experienced adverse events on nifedipine-PA versus 20 patients on nifedipine-GITS therapy. CONCLUSIONS: Patients whose hypertension is controlled by nifedipine-PA 10 or 20 mg bid can be successfully converted to nifedipine-GITS with most patients remaining normotensive on 30 mg daily.

Home or children's treatment centre: where should initial therapy assessments of children with disabilities be done?

Following developmental paediatric consultation at a child development clinic, 50 preschool children newly referred for a developmental rehabilitation programme were assigned randomly for initial therapist assessments at home or at the clinic. It was thought that children would perform more typically at home, that therapists would be able to observe more of the children's usual functions, and that parents would feel more satisfied. Despite several minor statistically significant differences between the two venues, there was no obvious advantage of home evaluation over clinic assessment. However, the added cost of home assessments was marginal, and there may still be some value in seeing young disabled children for first assessment in their own homes.

Efficacy and tolerability of tiapamil in patients with mild to moderate essential hypertension.

Although early experience with tiapamil, a new calcium antagonist structurally related to verapamil, showed good antihypertensive efficacy and minimal adverse effects, recent studies have shown conflicting results. This single-blind dose-titration study was designed to determine the therapeutic efficacy, duration of action, and safety profile of tiapamil in patients with essential hypertension. After a 2-week washout period, patients received placebo for 4 weeks. Patients with a sitting diastolic blood pressure (SDBP) of 95-114 mm Hg received tiapamil 300 mg twice daily with dose increments of 150 mg twice daily every 2 weeks to a maximum of 1,200 mg/day. Once blood pressure (BP) control was achieved or patients were receiving 600 mg twice daily, they were followed up for an additional 2 weeks. Twenty of the initial 31 patients completed the trial, and 17 patients were receiving the highest dose of tiapamil. Nine patients dropped out because of adverse effects. No significant decreases in BP and heart rate (HR) were either noted by the clinic or apparent by 24-h ambulatory BP readings. Random assays of drug supplies showed that patients received the required dosage. The incidence of adverse effects rose with increasing doses of tiapamil: 27.6% of patients at 300 mg twice daily, 48% at 450 mg twice daily, and 81.8% at 600 mg twice daily. Dizziness, headache, and palpitations were the most frequent adverse effects. These results show that tiapamil given at a daily dose of 600-1,200 mg exhibits very little effect in lowering BP in patients with mild to moderate essential hypertension. Moreover, the incidence of adverse effects is much higher than reported in earlier studies.

The effect of flumazenil on the recovery time of dental patients sedated with diazepam.

Flumazenil is an imidazobenzodiazepine that binds specifically to the central benzodiazepine receptor and antagonizes the actions of diazepam and other benzodiazepines. Previous studies in Europe have shown flumazenil at doses of 2 to 30 mg IV to reverse sedation in patients sedated with flunitrazepam, midazolam, and diazepam when evaluated by subjective criteria. The purpose of this study was to determine if flumazenil at 0.015 mg/kg IV was efficacious in shortening the recovery time of young, healthy dental patients sedated with diazepam (0.15 mg/kg IV) and restoring their psychomotor function to presedation levels. A total of 21 patients were randomized to placebo or flumazenil, sedated with diazepam, underwent a restorative dental procedure, and were then administered the test drug. Evaluations of psychomotor function by the Trieger test, Digit-Symbol Substitution test, Romberg test, and nurse questioning were carried out before sedation and at 10-minute intervals after test drug. Observations by the patients and nurses were not significantly different before versus after test drug. The investigator, however, found that flumazenil resulted in more rapid awakening. Patients treated with placebo exhibited significantly greater deficits in the number of dots missed and sum of deviations on the Trieger test than flumazenil-treated patients. Similar time-related deficits were recorded for the Digit-Symbol Substitution test. Flumazenil, at a dose of 0.015 mg/kg, was found to be efficacious in reducing the recovery time after diazepam sedation in dental patients.

Dietary sodium restriction and the renin-angiotensin system in young spontaneously hypertensive rats.

Severe dietary sodium restriction initiated early in life is required to prevent development of hypertension in spontaneously hypertensive rats (SHR). Moderate sodium restriction does not affect hypertension development. This relative insensitivity to sodium restriction may be related to compensatory increases in other pressor mechanisms, specifically the renin-angiotensin system. We evaluated this possibility by measuring plasma renin activity, the blood pressure response to the angiotensin converting enzyme inhibitor captopril as well as blood pressure responsiveness to exogenous angiotensin II in SHR and Wistar-Kyoto rats (WKY) raised from birth until 6 or 16 weeks on control (101 mumol Na+/g food), moderate (26 mumol/g) or two severe (17 or 9 mumol/g) sodium-restricted diets. Moderate sodium restriction did not affect development of hypertension, but also did not cause significant increases in PRA or the blood pressure response to captopril in SHR or WKY. In contrast, severe sodium restriction blunted or prevented the development of hypertension in SHR and was associated with (1) marked increases in plasma renin activity (2) increased maintenance of blood pressure by the renin-angiotensin system (as assessed by captopril), and (3) a marked decrease in the blood pressure response to angiotensin II. We conclude that the relative insensitivity of hypertension development in SHR to dietary sodium restriction does not relate to a compensatory increase in the activity of the renin-angiotensin system. The moderate sodium restriction employed (26 mumol/g) may rather represent the lower end of the normal range.

Dietary sodium restriction, blood pressure and sympathetic activity in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were started at birth on sodium diets ranging from severely deficient (9 mumol) to a regular intake (101 mumol Na+/g food). Blood pressure and sympathetic activity were assessed at 6 and 16 weeks of age. At either age, SHR on 9 mumol Na+ failed to develop hypertension. Spontaneously hypertensive rats on 17 mumol Na+ exhibited significant blunting of the hypertension; SHR on 26 mumol showed a small amelioration. At 6 weeks, basal plasma noradrenaline was similar in SHR and WKY on 9 and 101 mumol Na+, whereas plasma adrenaline was increased in SHR at the lowest sodium level. At 16 weeks, both catecholamines were significantly increased in SHR on the 9 and 17 mumol sodium diet versus SHR on the control diet. Blood pressure responsiveness to noradrenaline was significantly decreased on 9 mumol Na+, but to a similar extent in both strains. In contrast, the blood pressure lowering effect of ganglionic blockade was markedly blunted in SHR on 9 mumol Na+ and to a lesser extent on 17 mumol Na+ (both for percentage and absolute decrease) and 26 mumol Na+ (only for absolute fall); however, this did not occur in WKY over the diet-range used. We conclude that a sodium-deficient diet from birth prevents/blunts the development of hypertension in SHR, at least partly by decreasing the pressor effect of the sympathetic nervous system.

Blood pressure responsiveness during the development of hypertension in the conscious spontaneously hypertensive rat.

Blood pressure responsiveness to iv noradrenaline and angiotensin II was studied in conscious, freely moving, age-matched spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats from 4 to 16 weeks of age. At 4 and 6 weeks the SHR showed small, but nonsignificant increases in responsiveness compared with WKY to both noradrenaline and angiotensin II. At 8 weeks they exhibited similar responses to the WKY. Subsequently, at 12 and 16 weeks decreased responsiveness to noradrenaline (nonsignificant) and angiotensin II (p less than 0.05 at 12 and 16 weeks) was observed in SHR versus WKY. At 16 weeks of age, hexamethonium caused potentiation of the blood pressure response to noradrenaline and angiotensin II, but to the same degree in the two strains. Captopril at this age did not elicit potentiation to noradrenaline or angiotensin II in either strain. These results indicate that there is no rise in blood pressure responsiveness to circulating pressor agents, parallel to the development of hypertension in SHR. Increased receptor occupancy or more active attenuating reflexes in SHR versus WKY appear not to be involved in the absence of hyperresponsiveness in intact conscious SHR at 16 weeks of age.

Free tyrosine levels of rat brain and tissues with sympathetic innervation following administration of L-tyrosine in the presence and absence of large neutral amino acids.

The tyrosine concentration of fasted rats was measured in plasma, brain and tissues receiving sympathetic innervation after L-tyrosine (200 mg/kg) was administered alone or in the presence of an equimolar cocktail containing isoleucine, leucine and valine. In the samples taken at 15, 30, 45, 60, 120 or 180 minutes, the highest concentrations of L-tyrosine were observed in plasma, heart, adrenal gland and kidney at 15 minutes, but in interscapular brown adipose tissue at 15 and 30 minutes and in brain at 15-60 minutes. The decline from peak concentrations was slower in brain, kidney and interscapular brown adipose tissue than in plasma, but in all tissues examined, control levels of free tyrosine were attained by 180 minutes postadministration . Competing large neutral amino acids reduced the maximal uptake of tyrosine in the brain by 48% but had no effect in the other tissues examined.