1. Hydroquinine pharmacokinetics after oral administration in adult patients with muscle cramps.
H J van Kan, P Smits, P H Jansen, C Tuinte, A L Verbeek. Eur J Clin Pharmacol. 2000 Jun; 56(3): 263-7. DOI: 10.1007/s002280000128. PMID: 10952483.
Objective: This study was conducted to determine the pharmacokinetic properties of hydroquinine after oral administration in adult patients with muscle cramps. The main reason for this study was the poor availability of pharmacokinetic data, hindering the design of studies to explore the possible relationship between hydroquinine concentrations and effects. Methods: Sixteen adult patients with a clinical history of muscle cramps were given once-daily oral doses of 300 mg hydroquinine hydrobromide for 4 days. Serum and saliva samples were taken following a predefined schedule until 24 h after the last dose. Urine was collected during the study period. Hydroquinine concentrations were measured, and calculations were made of pharmacokinetic parameters using non-linear curve fitting. Results: Pharmacokinetics of hydroquinine could be best described using a one-compartment open model. After oral administration, hydroquinine was rapidly absorbed (mean +/- SD: maximum concentration 2.43+/-0.68 mg/ 1; time to maximum concentration 1.4+/-1.2 h; lag time 0.54+/-0.50 h). With an elimination half-life of 10.9+/-6.1 h, steady-state was reached in several days. The distribution volume was 1.24+/-0.29 l/kg, total clearance was 6.7+/-3.2 l/h. The measured unbound hydroquinine fraction was 8.6+/-3.0%. No correlation was found between saliva and serum concentrations. Cumulative urinary excretion of unchanged hydroquinine 24 h after the first dose was 35.5+/-9.2 mg. Conclusion: Pharmacokinetic properties of hydroquinine are roughly similar to those of quinine. The unchanged fraction of hydroquinine excreted in urine is higher than that reported for quinine. Saliva hydroquinine concentrations could not be related to serum values. Steady-state trough or other fixed-time serum concentrations may prove useful for further optimisation of hydroquinine dosage.
2. Randomised controlled trial of hydroquinine in muscle cramps.
T de Boo, A I Wesseling, K C Veenhuizen, P H Jansen, A L Verbeek. Lancet. 1997 Feb 22; 349(9051): 528-32. DOI: 10.1016/s0140-6736(97)80085-2. PMID: 9048790.
Background: Although quinine and hydroquinine are commonly prescribed for muscle cramps, controlled clinical trials of these drugs have reported mixed findings about efficacy. We investigated hydroquinine therapy in otherwise healthy adults who had frequent, ordinary muscle cramps. Methods: This randomised, double-blind, placebo-controlled, parallel-group trial consisted of three consecutive 2-week periods: qualification, treatment, and washout, 68 women and 44 men who had at least three muscle cramps per week were enrolled. During the treatment period, participants were randomly assigned 300 mg daily dose of hydroquinine hydrobromide dihydrate (54 participants) or placebo (58). The frequency, severity (1-10), duration, and location of muscle cramps, as well as any side-effects, were recorded by participant in daily diaries. The primary outcome measures were the number of muscle cramps and the number of days during which the participants had muscle cramps (cramp-days). Findings: We excluded five participants from both groups from the analysis. Thus, data from 49 hydroquinine-group participants and 53 placebo-group participants were analysed. In both groups the total number of muscle cramps and the number of cramp-days decreased during the treatment period compared with the qualification period. However, these improvements were greater in the hydroquinine group than in the placebo group. The hydroquinine-group participants reported a median of 8 (95% CI 7-12) fewer cramps and median of 3 (1-4) fewer cramp-days, whereas those on placebo reported only 3 (0-5) fewer cramps and 1 (0-5) fewer cramp-days. 32 (65%) of participants in the hydroquinine group had a 50% or greater reduction in the number of muscle cramps. After the onset of cramps, hydroquinine did not reduce the severity or duration of cramps. We also found a sustained effect after treatment had stopped. Hydroquinine was well tolerated, and resulted in only mild side-effects. Interpretation: In our study, 300 mg hydroquinine was safe to take in the short-term and significantly more effective than placebo in the prevention of frequent, ordinary muscle cramps. This therapeutic effect outlasted the duration of treatment.
3. Novel chiral thiourea derived from hydroquinine and l-phenylglycinol: an effective catalyst for enantio- and diastereoselective aza-henry reaction.
Yingjie Lin, Zhonglin Wei, Hai-Feng Duan, Jingdong Wang, Yuxin Liu, Dapeng Liang, Jungang Cao. ACS Omega. 2021 Feb 18; 6(8): 5812-5824. DOI: 10.1021/acsomega.0c06233. PMID: 33681620.
A series of chiral thiourea bearing multiple H-bond donors derived from hydroquinine has been reported. The aza-Henry reaction of isatin-derived ketimines and long-chain nitroalkanes catalyzed by these chiral thioureas can achieve high enantioselectivity (78-99% ee) and excellent diastereoselectivity (up to 99:1). This work is the first report on long-chain nitroalkanes as substrates with excellent diastereoselectivity in metal-free catalytic systems.
