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Background: Preferred anticonvulsant used to treat and prevent fits in eclampsia currently is magnesium sulphate. Clinical monitoring of tendon reflexes, respiration rate and measuring hourly urine output should be done to ensures safe administration of magnesium sulphate Objective: This study was conducted to evaluate maternal outcomes of magnesium sulphate and diazepam use in the management of severe pre-eclampsia and eclampsia in Jimma University Specialized Hospital. Methods: A retrospective hospital based cross-sectional comparative study was conducted using data collection format. Data was collected from the hospital delivery care register and patient chart records of all pregnant women who presented with the diagnosis of severe pre-eclampsia and eclampsia in two years and three months period from January, 2010 to April, 2012. Data analysis was done by SPSS version 16.0. A P-value of

All psychiatric and general medical male patients referred to 2 hospitals in Basra, Iraq from September 2000 to April 200l were screened using the Alcohol Use Disorder Identification Test. A total of 189 men were identified as having alcohol-related problems. The majority were aged 30-49 years, and two-thirds had drunk alcohol for over 10 years. About 53% of patients exceeded 1 bottle (750 mL) of spirits daily, and 14.8% reported morning drinking. Elevation of liver enzymes, hepatomegaly, jaundice and cirrhosis were identified in 46.0%. Liver cirrhosis was more common in patients drinking locally made arak. Many of the patients suffered psychiatric disorders, including anxiety disorders, depression and suicide attempts, and 80.9% took other psychoactive drugs. [ABSTRACT FROM AUTHOR]

Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter- and intra-individual pharmacokinetic (PK) variability are not well-characterized in children. We investigated the effects of genetic and non-genetic factors, including demographic, treatment duration, baseline clinical, and biochemical characteristics, on the PKs of EFV through population-PK modeling. Antiretroviral therapy (ART) naïve HIV infected children, 3-16 years (n = 100), were enrolled in Ethiopia and received EFV-based combination ART. EFV concentrations after the first dose and at steady-state collected over a span of 1 year were modeled using population-based methods. A one-compartment model with first-order absorption kinetics described the observed EFV data adequately. The CYP2B6*6 and ABCB1c.4036A>G genotypes were identified as major factors influencing EFV clearance. The typical estimates of oral clearance, volume of distribution, and absorption rate constant for typical 22 kg children with CYP2B6 *1/*1 and ABCB1c.4036G/G genotypes were 4.3 L/h, 124 L, and 0.776/h, respectively. Clearance was reduced by 28% and 72% in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively. Compared to week 1, clearance was higher from weeks 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes, respectively. Simulations indicated that EFV 12-h concentrations were comparable across weight bands, but more than 80% of subjects with CYP2B6*6/*6 had EFV concentrations greater than 4 μg/mL. EFV PK variability among children is partly explained by body weight, treatment duration, CYP2B6*6, and ABCB1 rs3842 genotypes. Therefore, in addition to body weight, pediatric dosing of EFV should consider pharmacogenetic variability, duration of therapy, and individual treatment outcomes., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: The aim: To compare efficacy of intramuscular (IM) versus intravenous (IV) ketamine for sedation in children undergoing brain MRI scanning in children., Patients and Methods: Materials and methods: Children who required elective brain MRI were selected for this study. They were randomly divided into two groups; group I received 1.5 mg/kg IV Ketamine and group II received 4 mg/kg IM ketamine. In each group supplementary 0.1 mg/kg midazolam intravenously before positioning on MRI table was given. Patients were monitored for pulse rate, SPO2, and respiratory wave., Results: Results: Children who received IM ketamine had significantly shorter scan time and a greater success rate of sedation with first dose than the IV group. The proportions of scan interruption and scan repeat were significantly higher among the IV group than in the IM group. The scan time was longer among the IV group than in the IM group with significantly more scan interruption and repeat. Satisfaction with sedation as expressed by the technicians was significantly more in the IM group than in IV group (98.1% vs. 80.8%, P= 0.004)., Conclusion: Conclusions: Intramuscular ketamine injection was predicted to have a better sedative success rate and takes less time to complete than intravenous admin¬istration. This makes IM ketamine more appealing in certain conditions.

(1) Background: Hepatocellular carcinoma (HCC) is one of the deadliest cancers globally, killing over 700,000 people each year. Despite the rising incidence and mortality rates of HCC in Ethiopia, only few single-centered studies have been conducted; therefore, we aimed to explore the clinicopathological characteristics and survival of patients with HCC in multicenter settings. (2) Methods: We conducted a retrospective analysis of 369 patients with confirmed HCC diagnosed between 2016 and 2021. The survival of patients weas determined using the Kaplan−Meier method, and hazard ratios of the prognostic factors were estimated in Cox proportional hazard models. (3) Results: Majority patients were male (67%) and had a mean age of 52.0 ± 15.6 years. The majority of patients (87%) had a large tumor size (>5 cm) at diagnosis and presented with an advanced-stage condition. Cirrhosis (58%) and viral hepatitis (46.5%) were the main risk factors associated with HCC. The median overall survival was 141 days (95% CI: 117−165). Patients who took antivirals for HBV had a higher survival benefit compared to the untreated group (469 vs. 104 days; p < 0.001). The risk of death was 12 times higher in patients with Barcelona Clinic Liver Cancer-D (BCLC-D) terminal stage HCC compared to patients with an early stage (BCLC-A) HCC. The stage of HCC and treatment against HBV are the most significant survival predictors. (4) Conclusions: The overall survival of HCC patients in Ethiopia is poor. Cirrhosis and viral hepatitis are the primary risk factors linked with HCC. Patients who received antiviral therapy for HBV had a better survival outcome.

The aim of the present study was to investigate the effects of exogenous glucocorticoids (GCs), a potent cause of male hypogonadism, on the function of the hypothalamic-pituitary-gonadal axis, and to determine their secondary effects in male patients. The present study was a case-controlled study conducted in Basrah, Iraq. Of the 152 participants who met the inclusion criteria, 100 patients used different types of GCs. Of these 100 patients, 57 patients (57%) were current GC users, and 43 patients (43%) were not currently using GCs (had not used GCs in the past 30 days). The control group was comprised of 52 men (34.21%), considered as healthy participants, although 7 men (13.65%) were biochemically diagnosed with hypogonadism. Current GC exposure significantly decreased the total and free testosterone levels, whereas previous GC exposure increased estradiol (E2) levels, with the 31 patients on oral dexamethasone (cumulative dose, 18.9 mg) exhibiting a 7.5-fold increased risk of being diagnosed with hypogonadism. For previous GC users, a significant increase in the E2 level was observed, whereas all other gonadal hormonal levels were within normal reference ranges, including the total and free testosterone levels. The total cumulative dose of equivalent GCs was 240 mg, which resulted in a decrease in total testosterone levels, and subsequent hypogonadism. Oral dexamethasone at a lower total cumulative dose resulted in hypogonadism., (Copyright: © Mohammed et al.)

Cyclophosphamide (CPA) containing chemotherapy regimen is the standard of care for breast cancer treatment in sub-Saharan Africa. Wide inter-individual variations in pharmacokinetics (PK) of cyclophosphamide (CPA) influence the efficacy and toxicity of CPA containing chemotherapy. Data on the pharmacokinetics (PK) profile of CPA and its covariates among black African patients is lacking. We investigated population pharmacokinetic/pharmacogenetic/pharmacodynamic (PK-PG-PD) of CPA in Ethiopian breast cancer patients. During the first cycle of CPA-based chemotherapy, the population PK parameters for CPA were determined in 267 breast cancer patients. Absolute neutrophil count was recorded at baseline and day 20 post-CPA administration. A population PK and covariate model analysis was performed using non-linear mixed effects modeling. Semi-mechanistic and empiric drug response models were explored to describe the relationship between the area under concentration-time curve (AUC), and neutrophil toxicity. One compartment model better described CPA PK with population clearance and apparent volume of distribution (V D ) of 5.41 L/h and 46.5 L, respectively. Inter-patient variability in CPA clearance was 54.5%. Patients carrying CYP3A5*3 or *6 alleles had lower elimination rate constant and longer half-life compared to wild type carriers. CYP2C9 *2 or *3 carriers were associated with increased clearance of CPA. Patients who received 500 mg/m 2 based CPA regimen were associated with a 32.3% lower than average clearance and 37.1% lower than average V D compared to patients who received 600 mg/m 2 . A 0.1 m 2 unit increase in body surface area (BSA) was associated with a 5.6% increment in V D . The mean V D (33.5 L) in underweight group (BMI < 18.5 kg/m 2 ) was significantly lower compared to those of overweight (48.1 L) or obese patients (51.9 L) ( p < 0.001). AUC of CPA was positively correlated with neutropenic toxicity. In conclusion, we report large between-patient variability in clearance of CPA . CYP3A5 and CYP2C9 genotypes, BSA, BMI, and CPA dosage regimen influence PK of CPA. Plasma CPA exposure positively predicts chemotherapy-associated neutropenic toxicity., (Copyright © 2020 Ahmed, Makonnen, Bisaso, Mukonzo, Fotoohi, Aseffa, Howe, Hassan and Aklillu.)

Tamoxifen displays wide inter-individual variability (IIV) in its pharmacokinetics and treatment outcome. Data on tamoxifen pharmacokinetics and pharmacogenetics from black African breast cancer patient populations is lacking. We investigated the pharmacokinetic and pharmacogenetic profile of tamoxifen and its major active metabolite, endoxifen, in Ethiopian breast cancer patients. A total of 81 female breast cancer patients on adjuvant tamoxifen therapy were enrolled. Tamoxifen (Tam) and its major metabolites, N-desmethyltamoxifen (NDM), 4-hydroxy-tamoxifen (4-HT), and ( Z )-endoxifen (E) were quantified using LC-MS/MS. Genotyping for CYP2D6, CYP2C9, CYP2C19, CYP3A5, POR, and ABCB1 and UGT2B1 5 and copy number variation for CYP2D6 were done. The proportion of patients with low endoxifen level (<5.9 ng/mL) was 35.8% (median concentration 7.94 ng/mL). The allele frequency of CYP2D6 gene deletion (*5) and duplication (*1×N or *2×N) was 4.3% and 14.8%, respectively. Twenty-six percent of the patients carried duplicated or multiplicated CYP2D6 gene. An increase in CYP2D6 activity score was associated with increased endoxifen concentration and MR E/NDM ( p < 0.001). The IIV in endoxifen concentration and MR E/NDM was 74.6% and 59%, respectively. CYP2D6 diplotype explained 28.2% and 44% of the variability in absolute endoxifen concentration and MR E/NDM , respectively. The explanatory power of CYP2D6 diplotype was improved among ABCB1c . 4036G carriers (43% and 65.2%, respectively for endoxifen concentration and MR E/NDM ) compared to A/A genotype. CYP2C9 , CYP2C19 , and CYP3A5 genotypes had no significant influence on endoxifen concentration or MR E/NDM. In conclusion, we report a high rate of low endoxifen level as well as large IIV in tamoxifen and its metabolite concentrations. CYP2D6 is significant predictor of plasma endoxifen level in a gene-dose dependent manner.

Chemotherapy-induced hematologic toxicity is the primary reasons of dose reductions and/or delays, low relative dose intensity (RDI), and predicts anticancer response. We investigated the incidence and predictors of chemotherapy-induced hematologic toxicities and reduced RDI in Ethiopian breast cancer patients, and implication of pharmacogenetics variations. Breast cancer patients ( n = 249) were enrolled prospectively to receive cyclophosphamide based chemotherapy. Hematological toxicity (neutropenia, anemia, and thrombocytopenia) were monitored throughout chemotherapy cycle. The primary and secondary outcomes were incidence of grade 3 or 4 toxicity and reduced RDI, respectively. CYP2B6 ∗ 6, CYP3A5 ∗ 3, CYP2C9 ( ∗ 2, ∗ 3 ), CYP2C19 ( ∗ 2, ∗ 3), CYP2J2 ∗ 7, POR ∗ 28 , and ABCB1 (rs3842) genotyping were done. Cox proportional hazard and logistic regression were used to estimate risk predictors of toxicity and reduced RDI, respectively. Majority (73.5%) of the patients were < 45 years of age. The incidence of grade 3 or 4 hematological toxicity was 51.0% (95% CI = 44.54-57.46%). Multivariate Cox proportional hazard regression indicated CYP2J2 ∗ 7 genotype [Hazard ratio (HR) = 1.82; 95% CI = 1.14-2.90], pretreatment grade 1 leukopenia (HR = 2.75; 95% CI = 1.47-5.15) or grade 1 or 2 neutropenia (HR = 2.75; 95% CI = 1.73-4.35) as significant predictors of hematologic toxicities. The odds of having hematologic toxicities was lower in CYP2C9 ∗ 2 or ∗ 3 carriers ( p = 0.024). The prevalence of reduced RDI was 56.6% (95% CI = 50.3-62.9%). Higher risk of reduced RDI was associated with CYP2J2 ∗ 7 allele [Adjusted odds ratio (AOR) = 2.79; 95% CI = 1.21-6.46], BMI ≤ 18.4 kg/m 2 (AOR = 5.98; 95% CI = 1.36-26.23), baseline grade 1 leukopenia (AOR = 6.09; 95% CI = 1.24-29.98), and baseline neutropenia (AOR = 3.37; 95% CI = 1.41-8.05). The odds of receiving reduced RDI was lower in patients with CYP2B6 ∗ 6/ ∗ 6 genotype (AOR = 0.19; 95% CI = 0.06-0.77). We report high incidence of chemotherapy-induced hematological toxicities causing larger proportion of patients to receive reduced RDI in Ethiopian breast cancer patients. Patients carrying CYP2J2 ∗ 7 allele and low baseline blood counts are at a higher risk for chemotherapy-induced hematologic toxicities and receiving reduced RDI, and may require prior support and close follow up during chemotherapy.

Emerging evidence associates vitamin D deficiency and vitamin D receptor ( VDR ) genetic variations with risk for breast cancer. This study investigated the prevalence of vitamin D deficiency and its association with tumor characteristics and the implications of VDR genetic variations for risk of breast cancer in Ethiopia. This unmatched case⁻control study involved 392 female breast cancer patients and 193 controls. The plasma 25-hydroxyvitamin D (25(OH)D₃) level was quantified in chemotherapy-naïve ( N = 112) and tamoxifen-treated patients ( N = 89). Genotyping for the VDR common variant alleles rs7975232 ( Apa I), rs2228570 ( Fok I), and rs731236 ( Taq I) was done. Eighty-six percent of the patients were vitamin D deficient (<50 nmol/L). Chemotherapy-naïve breast cancer patients had a higher prevalence of vitamin D deficiency (91.9% vs. 78.3%) compared to the tamoxifen-treated group ( p < 0.001). The prevalence of severe vitamin D deficiency (<25 nmol/L) was significantly higher in chemotherapy-naïve (41.1%) than tamoxifen-treated (11.2%) patients. Vitamin D deficiency was not significantly associated with tumor characteristics or VDR genotype. The rs2228570 GG genotype was associated with increased risk of breast cancer (OR = 1.44, 95% confidence interval = 1.01-2.06). Our result indicates that rs2228570 might be a moderate risk factor for breast cancer development in the Ethiopian population. The high prevalence of severe vitamin D deficiency in treatment-naïve breast cancer patients indicates the need for nutritional supplementation of vitamin D at the time of chemotherapy initiation.

Aim: To evaluate the protective effect of Nigella sativa (NS) against nephrotoxicity of methotrexate (MTX) in mice., Materials and Methods: Four groups of Swiss albino male mice, eight in each group were used. The study was carried on between October 2014 and April 2015. Group 1 (control) were administered 0.3 ml distilled water orally daily for 21 days and injected with normal saline (0.25 ml) IP weekly. Group 2 (MTX group) were treated with MTX, 10 mg/kg IP weekly, while Group 3 were treated with 0.125 ml of NS oil by mouth daily and injected with normal saline (0.25 ml) IP weekly. Group 4 received 0.125 ml of NS oil by mouth daily and injected with 10 mg/kg MTX IP weekly. Oral treatments were administered using a special curved smooth tip nontraumatic metal needle and IP injections were given for 3 weeks at days 7, 14 and 21. Animals were sacrificed at day 23. Malondialdehyde (MDA) and glutathione (GSH) measurements were performed on kidney homogenate. Histopathology of the kidneys were prepared and examined., Results: MTX has resulted in a small elevation in MDA and reduction in GSH levels in kidney homogenate which was returned back to control values when NS and MTX were administered in combination. Statistical significance was achieved with elevation of GSH by MTX and NS compared to MTX alone. MTX caused histopathological changes suggesting nephrotoxicity in 6 animals out of 8, while no changes were found in all animals treated with MTX and NS., Conclusion: NS is protective against MTX-induced nephrotoxicity., Competing Interests: Conflicts of Interest: None declared.

Objectives: To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity., Materials and Methods: Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed., Results: Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments., Conclusion: Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection.

Purpose The purpose of this article was to assess the pattern of supplement use and associated factors among pregnant women in Ethiopia. Methods A facility-based cross-sectional study was conducted. A total of 339 pregnant women were included in the study, 63 (18.3%) and 23 (6.8%) of whom used at least 1 supplement during pregnancy and 2 to 4 weeks prior to pregnancy, respectively. Only 3 women were prescribed folic acid during pregnancy. The pregnant women were interviewed to collect supplements use and pregnancy-related information through a pretested semistructured questionnaire. Subsequent charts of prescribed supplements were reviewed using a pretested data collection format. Results The majority (76.4%) of the women claimed no awareness about the benefits of early supplementation. Supplement use was about 8 times higher among women with > 3 children (adjusted odds ratio, 7.85; 95% confidence interval, 1.69-36.28; P = .008) than among nulliparous women, and about 6 times higher among women in their second trimester (adjusted odds ratio, 6.26; 95% confidence interval, 1.91-20.55; P = .03) of pregnancy compared to those women in their first trimester. Conclusion Overall supplement use, particularly folic acid intake, was found to be negligible during the prenatal as well as antenatal periods. The majority of the women in the study lacked awareness about the benefits of supplementation and potential risks associated with the absence of folic acid during pregnancy. Information by the media and health care personnel given to childbearing women about the need to take folic acid to prevent neural tube defects seems to improve the intake of folic acid during the protective period.

Objective: To investigate the possibility of hepatoprotective effect of Nigella sativa (NS) in INH-induced hepatotoxicity., Materials and Methods: The experiments were carried out on 24 male rabbits. They were divided into 4 groups (6 each); rabbits in group 1 were treated with INH following a standard protocol to induce hepatotoxicity. Rabbits in group 2 received starch. Group 3 received NS 1 g/kg/day before INH treatment. Group 4 rabbits were treated with NS only. Phenobarbital sodium (IP) was given to induce metabolism of INH. INH and NS were given orally. The experiment continued for 12 days; at day 13, animals were sacrificed. Liver function tests, malondialdehyde (MDA) were estimated in serum and in liver homogenates. Liver histopathological examinations were performed., Results: Histopathological changes of hepatotoxicity were found in all INH-treated rabbits. The histopathological findings were normal in three rabbits treated with NS before INH, very mild in two, and with moderate changes in one rabbit. Serum alanine aminotransferase (S.ALT) was elevated after INH treatment and returned back to the control value when NS was given before INH. Similar pattern of effect was noticed with serum aspartate aminotransferase (S.AST), S. total bilirubin, S. MDA, and Serum alkaline phosphatase.In liver homogenate, AST, ALT, and MDA were increased with INH treatment compared to the control, then decreased with NS treatment given before INH CONCLUSIONS: NS has hepatoprotective effects against INH-induced hepatotoxicity in rabbits. NS 1 g/kg proved safe, no adverse effects; no histopathological or biological abnormalities were seen.

Introduction: Various drugs have been investigated in the treatment of sickle cell disease (SCD), such as hydroxyurea, piracetam and calcium antagonists. Most of these drugs are potentially toxic and are not suitable for long-term therapy. Recently, Nigella sativa (NS) has been reported to have calcium antagonist and antioxidant activities, both of which play a role in the management of the disease. This study aimed to investigate the in vitro antisickling effect of extracts from NS., Methods: Thirty-two patients with SCD, aged 7-47 years old, were recruited for the study. A total of 3 ml of venous blood was collected from each patient and divided into six tubes with heparin. The blood was mixed with 0.5 ml of either 0.1 percent, 0.05 percent or 0.01 percent v/v of the oil extract of NS. A slide was prepared by spreading a drop of treated blood, covered with a cover slide to ensure the complete deoxygenation condition. The separation of irreversibly sickled cells (ISCs) was performed on eight patients by a density gradient (Percoll-Renografin) centrifugation method., Results: The 0.1 percent v/v concentration of the oil extract of NS resulted in an approximately 80 percent reduction in the formation of sickle cells. The 0.05 percent v/v concentration of NS produced an intermediate effect, while the 0.01 percent v/v concentration had no effect on the formation of sickle cells. The 0.1 percent v/v concentration of the fixed oil of NS led to a considerable reduction in the formation of ISCs., Conclusion: The fixed oil extracted from NS seeds has an in vitro antisickling activity.

One hundred and seven cases, 35 males and 72 females aging from 3 months to 32 years old were divided into 4 groups: ocular, neurological, cases with abortion and cases having Down's syndrome. 47 apparently healthy individuals were taken as control. All were serologically tested for Toxoplasma antibodies using IFAT and ELSA for detection of IgG. The positive cases as well as cases below one year old were tested by ELISA IgM for the detection of acute or congenital toxoplasmosis. Toxoplasma antibodies (IgG) were found in 28 (26%) and 43 cases (40%) by IFAT and ELISA respectively. ELISA IgM was positive in 12 (20%) out of 60 serum samples. Two cases (11%) among 27 patients below one year old positive. Statistical significance was reported concerning the positive cases in the ocular group as well as patients with abortions. Results revealed that ELISA is more sensitive and specific than IFAT.

In a placebo-controlled, double-blind, randomised, cross-over study the metabolic and hormonal responses to standard food and exercise challenge have been evaluated in seven patients with mild to moderate essential hypertension after treatment with nicardipine 30 mg three times daily for four weeks. There were no significant differences between nicardipine and placebo for any of the measured hormonal and metabolic indices following food or exercise. These results indicate that nicardipine has no clinically important effects on serum lipids or hormonal or metabolic responses to food and exercise.

This study investigated the cardiac responses and pharmacokinetics following the acute and chronic administration of verapamil in 14 middle-aged and elderly patients with ischemic heart disease (age range 42-76 years). There were small significant reductions in heart rate during chronic treatment, but there were no significant effects on the PR intervals following either single intravenous administration or after 4 weeks continued treatment. Left ventricular ejection fractions at rest or exercise were not significantly changed following either acute intravenous (rest 33%; exercise 38%) or chronic oral dosing with verapamil (rest 35%; exercise 43%) when compared with placebo (rest 34%; exercise 42%). There were no independent age-related effects on these indices of cardiac function, nor on apparent liver blood flow, nor on blood pressure and heart rate. The plasma clearance of verapamil was reduced from 1.3 l/min after acute dosing to 0.8 l/min during chronic treatment, but there was no significant independent age-related effect. The results of this study suggest that middle-aged and elderly patients with ischemic heart disease do not show enhanced cardiovascular responses to low doses (5 mg intravenously and 80 mg tid orally) of the calcium antagonist drug, verapamil.

The influence of age on the pharmacokinetics of verapamil at steady state has been studied in 74 individuals, age range 19-79 years, including healthy normotensive volunteers and patients with essential hypertension. The peak plasma concentrations (Cmax) of verapamil were significantly higher in older subjects (r = 0.24; P = 0.03) and there was a non-significant age-related decrease in clearance/F and a non-significant increase in elimination half-life. These results suggest that increasing age is associated with changes in the pharmacokinetics of verapamil but these changes are small and unlikely to be of clinical significance.

Pharmacokinetic and pharmacodynamic variability account for the large interindividual differences in the antihypertensive response to treatment with a calcium antagonist. Using an integrated kinetic-dynamic model, the acute and chronic (4-6 weeks) responses to nifedipine (n = 14) and verapamil (n = 14) were characterized for individual hypertensive patients in terms of fall in blood pressure per unit drug concentration. The responsiveness to nifedipine, as the mean of the group, was -0.48 mm Hg/ng/ml following the first dose and -0.49 mm Hg/ng/ml after chronic dosing. The corresponding values for verapamil were -0.13 and -0.12 mm Hg/ng/ml, respectively. For nifedipine and verapamil, the responsiveness to the first dose was significantly correlated both with the height of the pretreatment blood pressure (p less than 0.001) and the responsiveness after 4-6 weeks of treatment (p less than 0.001). Parameters derived from an individual approach to concentration-effect analysis are useful for evaluating the determinants of response to calcium antagonists and form a potential basis for optimizing drug therapy in individual patients.